Acetate salt of buprenorphine and methods for preparing buprenorphine

ABSTRACT

The present disclosure provides acetate salts of buprenorphine, and its anhydrates, solvates, hydrates, and crystalline forms thereof, where the acetate salts of buprenorphine are essentially free of impurities. The disclosure further provides method of preparing the acetate salts, buprenorphine free base prepared from the acetate salts, other salts prepared from the free base, and pharmaceutical compositions thereof essentially free of impurities.

1. BACKGROUND

Buprenorphine is an opioid used to treat opioid addiction and controlpain, such as moderate pain. Traditional methods for the synthesis ofbuprenorphine use thebaine or oripavine as the starting material. Theseknown methods of buprenorphine synthesis typically result in a level ofimpurities that is higher than the level acceptable according toguidelines of the International Harmonisation of Technical Requirementsfor Registration of Pharmaceuticals for Human Use (“ICH”). Examples ofimpurities that can be present at unacceptable levels in preparations ofbuprenorphine include(4R,4aS,6R,7R,7aR,12bS)-3-(but-3-en-1-yl)-6-((S)-2-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-9-oland(4R,4aS,6R,7R,7aR,12bS)-3-(cyclopropylmethyl)-6-((S)-2-hydroxy-3,3-dimethylbutan-2-yl)-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol.Some methods of purification, such as chromatography, e.g., as disclosedin U.S. Pat. No. 8,492,547, may provide buprenorphine with an acceptablelevel of impurities but have associated higher costs or are difficult toapply on a commercial scale. Accordingly, there is a need foralternative pathways for preparing buprenorphine containing acceptablelevels of impurities.

2. SUMMARY

One aspect of the disclosure relates to an acetate salt ofbuprenorphine.

Another aspect of the disclosure relates to buprenorphine acetatetetrahydrate.

Another aspect of the disclosure relates to a crystalline form of theacetate salt of buprenorphine.

Another aspect of the disclosure relates to a crystalline form ofbuprenorphine acetate tetrahydrate.

Another aspect of the disclosure relates to a method for preparing anacetate salt of buprenorphine, comprising the steps of:

(a) contacting buprenorphine free base with a solution comprising aceticacid in a dissolution vessel to form an admixture, wherein the admixtureis at a temperature of from about 40° C. to about 80° C.;

(b) optionally filtering the admixture of step (a);

(c) adding an agent to the admixture produced in step (a) or (b) toprecipitate the acetate salt of buprenorphine; and

(d) isolating the acetate salt of buprenorphine precipitated in step(c).

Another aspect of the disclosure relates to a method for preparingbuprenorphine free base comprising the steps of:

(a) contacting an acetate salt of buprenorphine with a solution and abasic material to form an admixture;

(b) agitating the admixture of step (a) at a temperature of from about20° C. to about 90° C. to provide buprenorphine free base;

(c) isolating the buprenorphine free base of step (b); and

(d) optionally repeating steps (a) through (c) one or more times.

Another aspect of the disclosure relates to a method for preparingbuprenorphine free base comprising treating an acetate salt ofbuprenorphine at a pressure, temperature and for a time sufficient toremove the acetic acid and water, thereby providing the buprenorphinefree base.

Another aspect of the disclosure relates to a method for preparingbuprenorphine free base, comprising the steps of:

(a) dissolving an acetate salt of buprenorphine in a solution to form anadmixture;

(b) optionally filtering the admixture of step (a);

(c) adding a basic material to the admixture in step (a) or (b) to forma second admixture;

(d) adding an anti-solvent to the second admixture produced in step (c)to form a precipitate of the buprenorphine free base; and

(e) isolating the precipitate from step (d).

Another aspect of the disclosure relates to a method for preparingbuprenorphine free base comprising:

(a) heating an admixture of an acetate salt of buprenorphine and anaqueous solution to provide precipitated buprenorphine free base; and

(b) filtering the admixture of step (a).

Another aspect of the disclosure relates to a method for preparingbuprenorphine free base comprising:

(a) mixing an acetate salt of buprenorphine in a solvent to form anadmixture;

(b) refluxing the admixture at a reflux temperature and removing theacetate as acetic acid in the vapor phase;

(c) cooling the admixture to provide precipitated buprenorphine freebase; and

(d) isolating the buprenorphine free base.

Buprenorphine acetate hydrate or a composition containing buprenorphineacetate hydrate is useful for treating or preventing: pain,constipation, drug abuse, an addictive disorder, vomiting, respiratorydepression, or euphoria (each hereafter being a “Condition”).

3. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a thermal ellipsoid representation of buprenorphine acetatetetrahydrate with selected hydrogen bonds.

FIG. 2 shows a packing diagram of buprenorphine acetate tetrahydratewithin the unit cell.

FIG. 3 shows a stick representation of the components of thebuprenorphine acetate tetrahydrate crystal including the atom numberingscheme used.

FIG. 4 shows an X-ray powder diffraction (“XRPD”) pattern ofbuprenorphine acetate tetrahydrate obtained using CuKα radiation.

FIG. 5 shows a differential scanning calorimetry scan of buprenorphineacetate tetrahydrate at a heating rate of 10° C./min.

FIG. 6 shows an integral ratio determination of transition regions in adifferential scanning calorimetry scan of buprenorphine acetatetetrahydrate.

4. DETAILED DESCRIPTION

The invention includes the following:

(1) An acetate salt of buprenorphine.

(2) The acetate salt of buprenorphine of the above (1), comprising ahydrate.

(3) The acetate salt of buprenorphine of the above (2), wherein thehydrate comprises from 1 to 6 water molecules per molecule of theacetate salt of buprenorphine.

(4) The acetate salt of buprenorphine of the above (3), wherein thehydrate is a tetrahydrate.

(5) A purified acetate salt of buprenorphine of any one of the above (1)to (4).

(6) The purified acetate salt of buprenorphine of the above (5), whichis an essentially pure acetate salt of buprenorphine.

(7) A crystalline form of the acetate salt of buprenorphine of any oneof the above (1) to (6).

(8) A crystalline form of the acetate salt of buprenorphine of the above(4).

(9) The crystalline form of the above (8), characterized by an X-raypowder diffraction pattern obtained by exposure to CuKα radiationcomprising peaks at 20 angles substantially equivalent to at least thepeaks at 16.21 and 18.70, and having at least one additional peak at a20 angle substantially equivalent to the peaks at 8.77, 10.31, or 18.47.

(10) The crystalline form of the above (8), characterized by an X-raypowder diffraction pattern obtained by exposure to CuKα radiationcomprising peaks at 20 angles substantially equivalent to at least thepeaks at 8.77, 10.31, 16.21, 18.47, and 18.70, and having at least oneadditional peak at a 20 angle substantially equivalent to the peaks at6.38, 11.93, or 19.40.

(11) The crystalline form of the above (8), characterized by an X-raypowder diffraction pattern obtained by exposure to CuKα radiationcomprising peaks at diffraction angles substantially equivalent to atleast the peaks at those in the following table:

Position [°2Theta] 6.38 8.77 10.31 11.93 16.21 18.47 18.70 19.40

(12) The crystalline form of the above (8), which has an X-ray powderdiffraction pattern substantially the same as the X-ray powderdiffraction pattern shown in FIG. 4 when measuring using CuKα radiation.

(13) The crystalline form of any one of the above (8) to (12), whereinthe crystalline form exhibits a first transition region with at leastone peak position at from about 50° C. to about 140° C. as measured by aheat flow differential scanning calorimeter at a heating rate of about10° C. per minute.

(14) The crystalline form of any one of the above (8) to (13), whereinthe crystalline form exhibits a second transition region having a peakposition at from about 217° C. to about 225° C. as measured by a heatflow differential scanning calorimeter at a heating rate of about 10° C.per minute.

(15) The crystalline form of the above (14), which exhibits an integralratio of from about 7 to about 8 for the first transition region at fromabout 50° C. to about 140° C. relative to the second transition regionat from about 217° C. to about 225° C., wherein the integrals aredetermined over the temperature ranges of from about 35° C. to about180° C. and from about 203° C. to about 233° C., respectively.

(16) The crystalline form of the above (15), wherein the crystallineform exhibits an integral ratio of from about 7.1 to about 7.8.

(17) The crystalline form of any one of the above (8) to (16),characterized in that it is a monoclinic crystal.

(18) The crystalline form of the above (17), wherein the unit cellparameters are a=10.5±0.5 Å, b=10.9±0.5 Å, and c=14.4±0.5 Å.

(19) The crystalline form of the above (17), wherein the unit cellparameters are a=10.52±0.05 Å, b=10.92±0.05 Å, and c=14.44±0.05 Å.

(20) The crystalline form of any one of the above (17) to (19), whereinthe space group is P2₁.

(21) A pharmaceutical composition comprising the acetate salt ofbuprenorphine of any one of the above (1) to (6) or the crystalline formof any of the above (7) to (20), and a pharmaceutically acceptablecarrier.

(22) A method for treating pain, constipation, drug abuse, an addictivedisorder, vomiting, respiratory depression, or euphoria comprisingadministering to an animal in need thereof an effective amount of theacetate salt of buprenorphine of any one of the above (1) to (6), thecrystalline form of any of the above (7) to (20) or the pharmaceuticalcomposition of the above (21).

(23) A method for treating pain comprising administering to an animal inneed thereof an effective amount of the acetate salt of buprenorphine ofany one of the above (1) to (6), the crystalline form of any of theabove (7) to (20) or the pharmaceutical composition of the above (21).

(24) A method for preparing an acetate salt of buprenorphine, comprisingthe steps of:

(a) contacting buprenorphine free base with a solution comprising aceticacid in a dissolution vessel to form an admixture, wherein the admixtureis at a temperature of from about 40° C. to about 80° C.;

(b) optionally filtering the admixture of step (a);

(c) adding an agent to the admixture produced in step (a) or (b) toprecipitate the acetate salt of buprenorphine; and

(d) isolating the acetate salt of buprenorphine precipitated in step(c).

(25) The method of the above (24), wherein in step (a) the buprenorphinefree base is contacted with from about 2 mass equivalents to about 6mass equivalents of the solution comprising acetic acid relative to thestarting mass of the free base.

(26) The method of the above (24), wherein the buprenorphine free baseis contacted with from about 3 mass equivalents to about 5 massequivalents of the solution comprising acetic acid relative to thestarting mass of the free base.

(27) The method of any one of the above (24) to (26), wherein thesolution comprising acetic acid is an aqueous solution.

(28) The method of the above (27), wherein the aqueous solution has fromabout 40 wt % to about 70 wt % acetic acid relative to the weight of theaqueous solution.

(29) The method of the above (27), wherein the aqueous solution has fromabout 45 wt % to about 60 wt % acetic acid relative to the weight of theaqueous solution.

(30) The method of any one of the above (24) to (29), wherein in step(a) the admixture is at a temperature of from about 40° C. to about 80°C. for a period of time such that a substantial portion of thebuprenorphine free base has dissolved.

(31) The method of the above (30), wherein in step (a) the admixture isat a temperature of from about 45° C. to about 75° C. for a period oftime such that a substantial portion of the buprenorphine free base hasdissolved.

(32) The method of the above (30), wherein in step (a) the admixture isat a temperature of from about 50° C. to about 70° C. for a period oftime such that a substantial portion of the buprenorphine free base hasdissolved.

(33) The method of any one of the above (24) to (32), wherein in step(a) the admixture is agitated to accelerate dissolution of thebuprenorphine free base.

(34) The method of the above (24), wherein the admixture of step (a) isfiltered in step (b) in a filtration apparatus.

(35) The method of the above (34), wherein in step (b), the admixture ofstep (a) added to the filtration apparatus is at a temperature of fromabout 40° C. to about 80° C.

(36) The method of the above (34), wherein in step (b), the admixture ofstep (a) added to the filtration apparatus is at a temperature of fromabout 45° C. to about 75° C.

(37) The method of any one of the above (34) to (36), wherein anadditional volume of a solution comprising acetic acid is used to rinsethe dissolution vessel, the filtration apparatus or the dissolutionvessel and the filtration apparatus.

(38) The method of the above (37), wherein the additional volume of thesolution comprising acetic acid is from about 0.1 mass equivalents toabout 2.0 mass equivalents relative to the starting mass of thebuprenorphine free base in step (a).

(39) The method of the above (37), wherein the additional volume of thesolution comprising acetic acid is from about 0.3 mass equivalents toabout 0.5 mass equivalents relative to the starting mass of thebuprenorphine free base in step (a).

(40) The method of any one of the above (37) to (39), wherein theadditional volume of the solution is acetic acid in an aqueous solution.

(41) The method of the above (40), wherein the additional volume of thesolution comprising acidic acid is an aqueous solution comprising aceticacid present at from about 40 wt % to about 70 wt % relative to theweight of the solution.

(42) The method of any one of the above (24) to (41), wherein in step(c) the agent is selected from an anti-solvent, a seed crystal, andcombinations thereof.

(43) The method of the above (42), wherein the agent comprises ananti-solvent.

(44) The method of the above (43), wherein the anti-solvent compriseswater.

(45) The method of the above (43) or (44), wherein from about 0.2 massequivalents to about 8.0 mass equivalents of anti-solvent relative tothe starting mass of free base in step (a) are added to the admixture ofstep (a) or (b).

(46) The method of any one of the above (43) to (45), wherein theanti-solvent is added at within about 10° C. of the temperature of theadmixture of step (a) or step (b).

(47) The method of the above (46), wherein the anti-solvent is added ata temperature within about 5° C. of the temperature of the admixture ofstep (a) or step (b).

(48) The method of the above (42), wherein the agent comprises a seedcrystal.

(49) The method of the above (48), wherein the seed crystal comprises anacetate salt of buprenorphine.

(50) The method of the above (49), wherein from about 0.1 wt % to about5.0 wt % of seed crystal is added to the admixture of step (a) or (b)relative to the starting mass of the buprenorphine free base in step(a).

(51) The method of any one of the above (48) to (50), wherein theadmixture of step (a) or (b) is at a temperature of from about 40° C. toabout 80° C. when the seed crystal is added.

(52) The method of the above (51), wherein the admixture of step (a) or(b) is at a temperature of from about 55° C. to about 65° C. when theseed crystal is added.

(53) The method of the above (42), wherein a first amount of theanti-solvent is added followed by addition of the seed crystal.

(54) The method of the above (53), wherein the addition of the seedcrystal is followed by the addition of a second amount of theanti-solvent.

(55) The method of the above (53) or (54), wherein the first amount ofthe anti-solvent is from about 0.2 mass equivalents to about 2.0 massequivalents relative to the starting mass of the buprenorphine free basein step (a).

(56) The method of any one of the above (53) to (55), wherein from about0.1 wt % to about 5.0 wt % of the seed crystal is added relative to thestarting mass of the buprenorphine free base in step (a).

(57) The method of any one of the above (54) to (56), wherein the secondamount of anti-solvent is from about 1.0 mass equivalent to about 6.5mass equivalents relative to the starting mass of the buprenorphine freebase in step (a).

(58) The method of any one of the above (24) to (57), further comprisingcooling the admixture to a temperature of about 30° C. or lowerfollowing addition of the agent and prior to isolating the acetate saltof buprenorphine in step (d).

(59) The method of any one of the above (24) to (57), further comprisingadding a co-solvent to the admixture following the precipitation of step(c) and prior to the isolating of the acetate salt of buprenorphine instep (d).

(60) The method of the above (59), wherein the co-solvent is selectedfrom methanol, ethanol, isopropyl alcohol, and combinations thereof.

(61) The method of the above (59), wherein the co-solvent is isopropylalcohol.

(62) The method of any one of the above (59) to (61), further comprisingcooling the admixture to a temperature of about 30° C. or lowerfollowing addition of the co-solvent and prior to the isolating of theacetate salt of buprenorphine in step (d).

(63) The method of any one of the above (24) to (62), wherein theisolation in step (d) is accomplished by filtration.

(64) The method of any one of the above (24) to (63), further comprisingslurrying the acetate salt of buprenorphine obtained from the isolationof step (d) with a slurrying solution comprising water and an alcohol,and filtering the acetate salt therefrom.

(65) A buprenorphine acetate salt product obtained from the method ofany one of the above (24) to (64).

(66) The product of the above (65), wherein the product comprises about0.10 wt % or less of a compound of formula (10):

or a salt thereof.

(67) The product of the above (65) or (66), wherein the productcomprises about 0.10 wt % or less of a compound of formula (11):

or a salt thereof.

(68) The product of any one of the above (65) to (67), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (12):

or a salt thereof.

(69) The product of the above (68), wherein the product comprises about0.08 wt % or less of the impurity represented by the compound of formula(12) or a salt thereof.

(70) The product of any one of the above (65) to (69), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (14):

or a salt thereof.

(71) The product of any one of the above (65) to (70), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (13):

or a salt thereof.

(72) The product of any one of the above (65) to (71), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (15):

or a salt thereof.

(73) A pharmaceutical composition comprising the product of any one ofthe above (65) to (72) and a pharmaceutically acceptable carrier.

(74) A method for treating pain, constipation, drug abuse, an addictivedisorder, vomiting, respiratory depression, or euphoria comprisingadministering to an animal in need thereof an effective amount of theproduct of any one of the above (65) to (72) or the pharmaceuticalcomposition of the above (73).

(75) A method for treating pain comprising administering to an animal inneed thereof an effective amount of the product of any one of the above(65) to (72) or the pharmaceutical composition of the above (73).

(76) A method for preparing buprenorphine free base comprising the stepsof:

(a) contacting an acetate salt of buprenorphine with a solution and abasic material to form an admixture;

(b) agitating the admixture of step (a) at a temperature of from about20° C. to about 90° C. to provide buprenorphine free base;

(c) isolating the buprenorphine free base of step (b); and

(d) optionally repeating steps (a) through (c) one or more times.

(77) The method of the above (76), wherein in step (a), the acetate saltof buprenorphine is contacted with at least about 1 mass equivalent ofthe solution relative to the starting mass of the acetate salt in step(a).

(78) The method of the above (76) or (77), wherein the solution of step(a) comprises water and an alcohol.

(79) The method of the above (78), wherein the solution comprises fromabout 30 wt % to about 70 wt % alcohol in water.

(80) The method of the above (78), wherein the solution comprises fromabout 40 wt % to about 60 wt % alcohol in water.

(81) The method of any one of the above (78) to (80), wherein thealcohol is selected from methanol, ethanol, isopropyl alcohol, andcombinations thereof.

(82) The method of the above (81), wherein the alcohol is isopropylalcohol.

(83) The method of the above (76), wherein the basic material isselected from a hydroxide, carbonate, alkoxide, hydride, phosphate,borate, oxide, cyanide, silicate, amine, and combinations thereof.

(84) The method of the above (76), wherein the acetate salt ofbuprenorphine is contacted with from about 0.5 molar equivalents toabout 20 molar equivalents of basic material relative to starting molesof the acetate salt of buprenorphine in step (a).

(85) The method of the above (84), wherein the acetate salt ofbuprenorphine is contacted with from about 1 molar equivalent to about10 molar equivalents of basic material relative to the starting moles ofacetate salt of buprenorphine in step (a).

(86) The method of any one of the above (76) to (85), wherein theadmixture of step (a) is agitated in step (b) for from about 1 hour toabout 36 hours.

(87) The method of the above (86), wherein agitating step (b) takes fromabout 2 hours to about 8 hours.

(88) The method of the above (86) or (87), wherein in step (b) theadmixture is agitated at a temperature of from about 25° C. to about 90°C.

(89) The method of the above (88), wherein in step (b) the admixture isagitated at a temperature of from about 30° C. to about 45° C.

(90) The method of any one of the above (76) to (89), wherein theisolating in step (c) is accomplished by filtration.

(91) The method of any one of the above (76) to (90), further comprisinga step of slurrying the buprenorphine free base of step (c) with aslurrying solution comprising water and an alcohol, and filtering thefree base therefrom.

(92) A buprenorphine free base product obtained from the method of anyone of the above (76) to (91).

(93) The product of the above (92), wherein the product comprises about0.10 wt % or less of a compound of formula (10):

(94) The product of the above (92) or (93), wherein the productcomprises about 0.10 wt % or less of a compound of formula (11):

(95) The product of any one of the above (92) to (94), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (12):

(96) The product of the above (95), wherein the product comprises about0.08 wt % or less of the impurity represented by the compound of formula(12).

(97) The product of any one of the above (92) to (96), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (14):

(98) The product of any one of the above (92) to (97), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (13):

(99) The product of any one of the above (92) to (98), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (15):

(100) A pharmaceutical composition comprising the product of any one ofthe above (92) to (99) and a pharmaceutically acceptable carrier.

(101) A method for treating pain, constipation, drug abuse, an addictivedisorder, vomiting, respiratory depression, or euphoria comprisingadministering to an animal in need thereof an effective amount of theproduct of any one of the above (92) to (99) or a pharmaceuticalcomposition of the above (100).

(102) A method for treating pain comprising administering to an animalin need thereof an effective amount of the product of any one of theabove (92) to (99) or a pharmaceutical composition of the above (100).

(103) A method for preparing buprenorphine free base, comprisingtreating an acetate salt of buprenorphine at a pressure, temperature andfor a time sufficient to remove the acetic acid.

(104) The method of the above (103), wherein the pressure is asub-atmospheric pressure of from about 100 Torr to about 200 Torr.

(105) The method of the above (104), wherein the temperature is at leastabout 30° C. and the time is at least about 1 hour.

(106) The method of the above (105), wherein the temperature is at leastabout 50° C.

(107) The method of the above (105), wherein the temperature is at leastabout 65° C.

(108) The method of any one of the above (103) to (107), wherein thetreatment lasts at least about 5 hours.

(109) The method of the above (108), wherein the treatment is lasts atleast about 10 hours.

(110) The method of any one of the above (103) to (109), furthercomprising slurrying the buprenorphine free base with a slurryingsolution comprising water and an alcohol, and filtering the free basetherefrom.

(111) The method of the above (103), wherein the pressure is anatmospheric pressure of from about 620 Torr to about 780 Torr.

(112) The method of the above (111), wherein the temperature is fromabout 65° C. to about 100° C.

(113) The method of the above (111) or (112), wherein the treatmentlasts at least about 7 hours.

(114) The method of any one of the above (111) to (113), wherein thetreatment lasts long enough to form essentially pure buprenorphine freebase.

(115) The method of any one of the above (103) to (114), wherein aceticacid in the final buprenorphine free base product is present at lessthan about 0.5 wt %.

(116) A buprenorphine free base product obtained from the method of anyone of the above (103) to (115).

(117) A pharmaceutical composition comprising the product of the above(116) and a pharmaceutically acceptable carrier.

(118) A method for treating pain, constipation, drug abuse, an addictivedisorder, vomiting, respiratory depression, or euphoria comprisingadministering to an animal in need thereof an effective amount of theproduct of the above (116) or the pharmaceutical composition of theabove (117).

(119) A method for treating pain comprising administering to an animalin need thereof an effective amount of the product of the above (116) orthe pharmaceutical composition of the above (117).

(120) A method for preparing buprenorphine free base, comprising thesteps of:

(a) dissolving an acetate salt of buprenorphine in a solution to form anadmixture;

(b) optionally filtering the admixture of step (a);

(c) adding a basic material to the admixture in step (a) or (b) to forma second admixture;

(d) adding an anti-solvent to the second admixture produced in step (c)to form a precipitate of the buprenorphine free base; and

(e) isolating the precipitate from step (d).

(121) The method of the above (120), wherein the solution of step (a)comprises an organic solvent.

(122) The method of the above (121), wherein the organic solventcomprises an alcohol.

(123) The method of the above (122), wherein the organic solventcomprises an alcohol selected from the group consisting of methanol,ethanol, and isopropyl alcohol.

(124) The method of any one of the above (120) to (123), wherein theanti-solvent of step (d) comprises an aqueous solution.

(125) The method of any one of the above (120) to (124), wherein theacetate salt of buprenorphine is contacted with at least about 3 massequivalents of the solution relative to the starting mass of the acetatesalt of buprenorphine in step (a).

(126) The method of any one of the above (120) to (125), furthercomprising mixing the admixture of step (a) at a temperature of about20° C. to about 90° C. such that substantially all the acetate salt ofbuprenorphine is dissolved.

(127) The method of the above (126), wherein in step (a) the admixtureis at a temperature of at least about 40° C.

(128) The method of the above (126), wherein in step (a) the admixtureis at a temperature of at least about 50° C.

(129) The method of any one of the above (120) to (128), wherein theadmixture of step (a) is filtered in step (b).

(130) The method of any one of the above (120) to (129), wherein in step(c), from about 1.0 molar equivalent to about 20 molar equivalents ofbase relative to the starting number of moles of acetate salt ofbuprenorphine in step (a) are added to the admixture produced in step(a) or (b).

(131) The method of any one of the above (120) to (130), wherein in step(d), at least about 3 mass equivalents of the anti-solvent relative tothe starting mass of the acetate salt of buprenorphine in step (a) areadded to the second admixture produced in step (c).

(132) The method of any one of the above (120) to (131), wherein theisolating in step (e) is accomplished by filtration.

(133) The method of any one of the above (120) to (132), furthercomprising slurrying the free base obtained from the isolation of step(e) with a slurrying solution comprising water and an alcohol, andfiltering the free base therefrom.

(134) A buprenorphine free base product obtained from the method of anyone of the above (120) to (133).

(135) The product of the above (134), wherein the product comprisesabout 0.10 wt % or less of a compound of formula (10):

(136) The product of the above (134) or (135), wherein the productcomprises about 0.10 wt % or less of a compound of formula (11):

(137) The product of any one of the above (134) to (136), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (12):

(138) The product of the above (137), wherein the product comprisesabout 0.08 wt % or less of the compound of formula (12).

(139) The product of any one of the above (134) to (138), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (14):

(140) The product of any one of the above (134) to (139), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (13):

(141) The product of any one of the above (134) to (140), wherein theproduct comprises about 0.10 wt % or less of a compound of formula (15):

(142) A pharmaceutical composition comprising the product of any one ofthe above (134) to (141) and a pharmaceutically acceptable carrier.

(143) A method for treating pain, constipation, drug abuse, an addictivedisorder, vomiting, respiratory depression, or euphoria comprisingadministering to an animal in need thereof an effective amount of theproduct of any one of the above (134) to (141) or the pharmaceuticalcomposition of the above (142).

(144) A method for treating pain comprising administering to an animalin need thereof an effective amount of the product of any one of theabove (134) to (131) or the pharmaceutical composition of the above(142).

(145) A method for preparing buprenorphine free base comprising:

(a) heating an admixture of an acetate salt of buprenorphine and anaqueous solution to provide precipitated buprenorphine free base; and

(b) filtering the admixture of step (a).

(146) The method of the above (145), wherein the aqueous solutionconsists essentially of water.

(147) The method of the above (145), wherein the aqueous solutioncomprises a mixture of water and an alcohol.

(148) The method of the above (147), wherein the alcohol is isopropylalcohol.

(149) The method of any one of the above (145) to (148), wherein theheating is to a temperature of from about 70° C. to about 90° C.

(150) The method of the above (145) or (146), further comprising washingthe solid filtered product of step (b) with a second aqueous solution.

(151) The method of any one of the above (145) to (150), furthercomprising the step of drying the solid filtered product of step (b).

(152) A buprenorphine free base product obtained from the method of anyone of the above (145) to (151).

(153) A pharmaceutical composition comprising the product of the above(152) and a pharmaceutically acceptable carrier.

(154) A method for treating pain, constipation, drug abuse, an addictivedisorder, vomiting, respiratory depression, or euphoria comprisingadministering to an animal in need thereof an effective amount of theproduct of the above (152) or the pharmaceutical composition of theabove (153).

(155) A method for treating pain comprising administering to an animalin need thereof an effective amount of the product of the above (152) orthe pharmaceutical composition of the above (153).

(156) A method for preparing buprenorphine free base: comprising:

(a) mixing an acetate salt of buprenorphine in a solvent to form anadmixture;

(b) refluxing the admixture at a reflux temperature and removing theacetate as acetic acid in the vapor phase;

(c) cooling the admixture to provide precipitated buprenorphine freebase; and

(d) isolating the buprenorphine free base.

(157) The method of the above (156), wherein the isolating of step (d)comprises filtering the precipitated buprenorphine free base of step(c).

(158) The method of the above (156) or (157), wherein the solventcomprises an organic solvent.

(159) The method of the above (158), wherein the organic solventcomprises heptane.

(160) A buprenorphine free base product obtained from the method of anyone of the above (156) to (159).

(161) A pharmaceutical composition comprising the product of the above(160) and a pharmaceutically acceptable carrier.

(162) A method for treating pain, constipation, drug abuse, an addictivedisorder, vomiting, respiratory depression, or euphoria comprisingadministering to an animal in need thereof an effective amount of theproduct of the above (160) or the pharmaceutical composition of theabove (161).

(163) A method for treating pain comprising administering to an animalin need thereof an effective amount of the product of the above (160) orthe pharmaceutical composition of the above (161).

4.1 Definitions

As used herein, the following terms are intended to have the followingmeanings.

“Crystalline form” as used herein refers to anhydrous crystalline forms,partially crystalline forms, a mixture of crystalline forms, hydratecrystalline forms, and solvate crystalline forms.

“Polymorphs,” “polymorphic forms,” and related terms as used hereinrefer to two or more crystal forms that consist essentially of the samemolecule, molecules, and/or ions and include, but are not limited to,other solid state molecular forms such as hydrates and solvates.Different polymorphs can have different physical properties such as,e.g., melting temperature, heat of fusion, solubility, dissolutionproperties, and/or vibrational spectra, as a result of the arrangementor conformation of the molecules and/or ions in the crystal lattice. Thedifferences in physical properties may affect pharmaceutical parameterssuch as storage stability, compressibility, and density (important informulation and product manufacturing), and dissolution rate (animportant factor in bioavailability).

“Solvate” as used herein refers to a crystalline form of a compound,molecule, atom, ion, or salt thereof that further contains molecules ofa solvent incorporated into the crystalline structure. The solventmolecules in the solvate may be present in a regular arrangement or in anon-ordered arrangement. The solvate may comprise either astoichiometric or non-stoichiometric amount of the solvent molecules.For example, a solvate with a non-stoichiometric amount of solventmolecules may result from partial loss of solvent from the solvate.

“Hydrate” as used herein refers to a crystalline form of a compound,molecule, atom, ion, or salt thereof further containing one or morewater molecules in a three-dimensional arrangement. It can includenon-stoichiometric hydrates or stoichiometric hydrates, such as ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate,pentahydrate, or hexahydrate, or a hydrate where the ratio of water percompound or salt thereof is not necessarily an integer but, for example,any value ranging from 0.5 to 10.0. In some embodiments, the hydrate hasa ratio of water per compound or salt thereof of from 1 to 8. In someembodiments, the hydrate has a ratio of water per compound or saltthereof of from 1 to 5. In some embodiments, the hydrate has a ratio ofwater per compound or salt thereof of from 3 to 5, e.g., of 3.0, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5,4.6, 4.7, 4.8, 4.9, or 5.0.

“Anhydrous,” “anhydrate,” and related terms refer to a compound,molecule, atom, ion, or salt with no water or that is substantially freeof water. In some embodiments, “anhydrous” or “anhydrate” refers to awater content of less than about 1.0 wt % water by weight.

“Admixture” as used herein refers to the combined elements of themixture regardless of the phase-state of the combination (e.g., entirelyliquid or a slurry or, concurrently, liquid and solid).

“Seeding” as used herein refers to the addition of a crystallinematerial to an admixture, e.g., a solution, to initiaterecrystallization or crystallization.

“Anti-solvent” as used herein refers to a solvent or liquid in whichcompounds are poorly soluble to insoluble. An anti-solvent may be used,for example, to cause a solubilized compound to precipitate out ofsolution. One example of an anti-solvent can be water (see Example 2).

In reference to a compound or composition, “purified” as used hereinmeans the purity of a given compound. For example, a compound is“purified” when the given compound is a major component of thecomposition, i.e., at least 50 wt % of the preparation. Thus, “purified”embraces at least about 50 wt %, at least about 60 wt %, at least about65 wt %, at least about 70 wt %, at least about 75 wt %, at least about80 wt %, at least about 85 wt %, at least about 90 wt %, at least about92 wt %, at least about 94 wt %, at least about 96 wt %, at least about97 wt %, at least about 98 wt %, at least about 98.5 wt %, at leastabout 99.0 wt %, or at least about 99.5 wt % of a preparation being thecompound of interest.

In reference to a compound or composition, “essentially pure” as usedherein means at least 98 wt % of a preparation is the compound ofinterest. In some embodiments, a compound or composition is “essentiallymore pure” when at least 99 wt % of the preparation is the compound ofinterest.

In reference to a first compound or composition containing the firstcompound, “essentially free” of another compound as used herein meansthat the other compound is present in an amount that is no more than 1wt % of the amount of the first compound of interest.

“Crystallizing,” “crystallize,” “crystallization,” and related terms asused herein refer to a process of forming solid crystals precipitatingfrom a solution, where “crystal” refers to a solid material, where theconstituent compounds, salt, or solvates thereof are arranged in aregular pattern, which extends in all three spatial dimensions.

“Precipitating,” “precipitate,” “precipitation,” and related terms asused herein encompasses “crystallizing,” “crystallize,” and“crystallization” unless stated otherwise. In some embodiments, theprecipitate described herein is amorphous. In some embodiments, theprecipitate is a mixture of amorphous and crystalline components. Insome embodiments, the precipitate described herein is crystalline.

“Threshold amount,” “threshold limit,” and related terms as used hereinrefer to the reporting, identification, and acceptable limits ofimpurities, particularly organic impurities, in drug substances anddosage forms as set out in the latest version of the ICH Guidelines orby regulatory authorities, such as the U.S. Food and Drug Administration(“FDA”) and the European Medicines Agency (“EMA”), and can be obtainedfrom the latest version of the FDA or EMA monographs.

“Pharmaceutically acceptable” refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for administration to human beings or animalswithout excessive toxicity, irritation, allergic response, or otherproblem complications commensurate with a reasonable benefit/risk ratio.

“Salt” as used herein refers to a compound comprising at least one anion(e.g., an anion of acetic acid) and at least one cation (e.g., abuprenorphine cation resulting from protonation of buprenorphine freebase by a Brönsted acid (e.g., phosphoric acid)). A salt may be theresult of the neutralization reaction between an acid and a base (e.g.,a Brönsted acid and a Brönsted base, or a Lewis acid and a Lewis base).In its solid form, the salt may form by precipitation or may have acrystalline structure. The term “salt” encompasses all salts of thedisclosed compounds.

“Pharmaceutically acceptable salt” as used herein refers to anypharmaceutically acceptable salt that can be prepared from a compound orby a process of the disclosure, including a salt formed from an acid anda basic functional group, such as the nitrogen group of buprenorphine.Illustrative salts include, but are not limited, to sulfate, citrate,acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucoronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also includes a saltprepared from a compound having an acidic functional group, such as acarboxylic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, cesium, andlithium; hydroxides of alkaline earth metal such as calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia and organic amines, such as unsubstituted or hydroxy-substitutedmono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine;pyridine; picoline; N-methyl-N-ethylamine; diethylamine; triethylamine;mono-, bis-, or tris-(2-hydroxy-(C₁-C₃)alkyl amines), such as mono-,bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine,N,N-di-[(C₁-C₃)alkyl]-N-(hydroxy-(C₁-C₃)alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike.

In some embodiments, the pharmaceutically acceptable salt is ahydrochloride salt, a levulinic acid salt, a sulfate salt, an aceticacid salt, a sodium salt, a potassium salt, a benzene sulfonic acidsalt, a para-toluenesulfonic acid salt, or a fumaric acid salt. In someembodiments, the pharmaceutically acceptable salt is a hydrochloridesalt, a levulinic acid salt, an acetic acid salt, or a sulfate salt. Insome embodiments, the pharmaceutically acceptable salt is ahydrochloride salt. In some embodiments, the pharmaceutically acceptablesalt is a levulinic acid salt. In some embodiments, the pharmaceuticallyacceptable salt is an acetic acid salt. In some embodiments, thepharmaceutically acceptable salt is a sulfate salt. In some embodiments,the pharmaceutically acceptable salt is a sodium salt. In someembodiments, the pharmaceutically acceptable salt is a potassium salt.In some embodiments, the pharmaceutically acceptable salt is apara-toluenesulfonic acid salt. Various pharmaceutically acceptablesalts can be prepared by reaction of the compound with an appropriateacid according to the guidance in the present disclosure or by any of avariety of known methods in view of the present disclosure.

“Effective amount” as used herein in connection with a therapeutic agentrefers to an amount of the agent or compound of the disclosureadministered to an animal that provides a therapeutic effect.

“Treatment of,” “treating,” and related terms as used herein include theamelioration, reduction, slowing, or cessation of a Condition or asymptom thereof by administration of an effective amount of an agent orcompound of the disclosure. In some embodiments, treating includesinhibiting, for example, decreasing the overall frequency of episodes ofa Condition or a symptom thereof.

“Prevention of,” “preventing,” and related terms as used herein includethe avoidance of the onset of a Condition or a symptom thereof byadministration of an effective amount of an agent or compound of thedisclosure.

“Disorder” as used herein includes, but is not limited to, theConditions defined herein.

“Animal” as used herein includes, but is not limited to, a human or anon-human animal, such as a companion animal or livestock, e.g., a cow,monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail,cat, dog, mouse, rat, rabbit, or guinea pig. In one embodiment, ananimal is a human.

The term “C_(max)” denotes the maximum plasma concentration obtainedduring a dosing interval.

The term “bioavailability” is defined for purposes of the disclosure asthe relevant extent to which a drug (e.g., buprenorphine) is absorbedfrom a dosage form, e.g., a unit dosage form. Bioavailability is alsoreferred to as “AUC” (i.e., the area under the plasma concentrationversus time curve).

The term “molar equivalent” is defined for purposes of the disclosure asthe number of moles of “X” relative to the number of moles of “Y”. Forexample, 5 molar equivalents of X relative to Y signifies that if 1 moleof Y is used then 5 moles of X are used. One molar equivalent of Xrelative to Y signifies that if 1 mole of Y is used then 1 mole of X isused.

The term “mass equivalent” is defined for purposes of the disclosure asthe mass amount of “X” relative to the mass amount of “Y”. For example,4 mass equivalents of X relative to Y signifies that if 1 g of Y is usedthen 4 g of X are used. One mass equivalent of X relative to Y signifiesthat if 1 kg of Y is used then 1 kg of X is used.

The articles “a,” “an,” and “the” as used herein refer to one or morethan one of the species designated by the term following said articleunless otherwise clearly indicated by context. For example, “a compoundof formula (1)” encompasses one or more molecules of the compound offormula (1).

In the event of doubt as to the agreement of a depicted chemicalstructure and a chemical name, the chemical structure governs.

It is appreciated that various features of the disclosure which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment unless otherwisespecifically excluded herein. Conversely, various features of thedisclosure which are, for brevity, described in the context of a singleembodiment, can also be provided separately and/or in any suitablesubcombination unless otherwise specifically excluded herein.

4.2 Buprenorphine Acetate and Corresponding Hydrates

In some aspects, the disclosure provides new salts of buprenorphine. Inparticular, the new salts of the disclosure display superior propertiesand characteristics relative to other known salts of buprenorphine,e.g., as disclosed in Example 1 herein. In particular, the disclosureprovides an acetate salt of buprenorphine. Buprenorphine, i.e.,(4R,4aS,6R,7R,7aR,12bS)-3-(cyclopropylmethyl)-6-((S)-2-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ol,has the chemical structure of formula (1):

A mono-acetate salt of buprenorphine can be depicted as shown in formula(1a):

In some embodiments, the disclosure provides polymorphs of the acetatesalt of formula (1a). In some embodiments, a polymorph of the acetatesalt of formula (1a) can be an anhydrate, a solvate, or a hydrate.

In some embodiments, acetate salts of buprenorphine are hydratescomprising from 1 to 6 water molecules per molecule of acetate salt. Insome embodiments, each acetate salt of formula (1a) can be associatedwith 1, 2, 3, 4, 5, or 6 water molecules. In particular embodiments,each acetate salt of formula (1a) is associated with 4 water moleculesand is referred to herein as a tetrahydrate, which can be depicted byformula (1b):

In some embodiments, the stoichiometry of buprenorphine acetate saltmolecules to water molecules is calculated as an average or mean valuefor a given sample. For example, for a given sample of buprenorphineacetate hydrate, the stoichiometry averages about 4 water molecules perbuprenorphine acetate molecule. In some embodiments, the buprenorphineacetate hydrate has an average of about 3.5, about 3.6, about 3.7, about3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4,or about 4.5 water molecules per buprenorphine acetate molecule.

In some embodiments, the buprenorphine acetate is in an anhydrous form.In some embodiments, the anhydrate of buprenorphine acetate is“substantially free” of water. A preparation substantially free of watercan have an average stoichiometry of less than 0.40 molecules of waterper molecule of buprenorphine acetate salt, such as about 0.30 watermolecules or less, about 0.20 water molecules or less, about 0.10 watermolecules or less, about 0.05 water molecules or less, about 0.02 watermolecules or less, or about 0.01 water molecules or less. In someembodiments, the anhydrate of buprenorphine acetate that issubstantially free of water has less than about 1.0 wt %, less thanabout 0.7 wt %, less than about 0.5 wt %, less than about 0.4 wt %, orless than about 0.2 wt % water by weight.

In some embodiments, the buprenorphine acetate salt is in the form of apurified buprenorphine acetate salt. In some embodiments, the purifiedbuprenorphine acetate salt is at least about 50 wt %, at least about 60wt %, at least about 65 wt %, at least about 70 wt %, at least about 75wt %, at least about 80 wt %, at least about 85 wt %, at least about 90wt %, at least about 92 wt %, at least about 94 wt %, at least about 96wt %, or at least about 97 wt % of the weight of the preparation. Insome embodiments, the buprenorphine acetate salt is in the form of anessentially pure buprenorphine acetate salt as defined herein, e.g., atleast about 98 wt % or, in another embodiment, at least about 98.5 wt %of the weight of the preparation. In some embodiments, the buprenorphineacetate salt is in the form of an essentially more pure buprenorphineacetate salt as defined herein, e.g., at least about 99.0 wt % or, inanother embodiment, at least about 99.5 wt % of the weight of thepreparation.

In some embodiments, the buprenorphine acetate salt of the disclosure isa crystalline form of the buprenorphine acetate salt, such as acrystalline form of an anhydrate, hydrate, or solvate of thebuprenorphine acetate salt. In some embodiments, the buprenorphineacetate salt is a crystalline form of a hydrate of buprenorphine acetatesalt, where the hydrate can have the number of water molecules permolecule of acetate salt, such as 1, 2, 3, 4, 5, or 6 water moleculesper molecule of acetate salt. In some embodiments, a crystalline form isthe tetrahydrate depicted in formula (1b), shown above.

In some embodiments, the crystalline form of buprenorphine acetate saltis characterized by an X-ray powder diffraction (“XRPD”) patternobtained using CuKα radiation comprising one or more peaks atdiffraction angles substantially equivalent to those in Table 1.

TABLE 1 Position [°2θ] Relative Intensity [%] 6.38 10 8.77 32 10.31 2411.93 19 16.21 100 18.47 25 18.70 53 19.40 14

In some embodiments, the crystalline form of buprenorphine acetate saltis characterized by an XRPD pattern, obtained using CuKα radiation,comprising one or more peaks at 20 angles substantially equivalent to6.38, 8.77, 10.31, 11.93, 16.21, 18.47, 18.70, and 19.40. In someembodiments, the crystalline form of buprenorphine acetate salt ischaracterized by an XRPD pattern, obtained using CuKα radiation,comprising peaks at 20 angles substantially equivalent to at least thepeaks at 16.21 and 18.70, and having at least one additional peak at a20 angle substantially equivalent to at least one of the peaks at 8.77,10.31, or 18.47. In some embodiments, the crystalline form ofbuprenorphine acetate salt is characterized by an XRPD pattern, obtainedusing CuKα radiation, comprising peaks at 20 angles substantiallyequivalent to at least the peaks at 16.21 and 18.70, and having at leasttwo additional peaks at 20 angles substantially equivalent to at leasttwo of the peaks at 8.77, 10.31, or 18.47. In some embodiments, thecrystalline form of buprenorphine acetate salt is characterized by anXRPD pattern, obtained using CuKα radiation, comprising peaks at 20angles substantially equivalent to at least the peaks at 8.77, 10.31,16.21, 18.47, and 18.70.

In some embodiments, the crystalline form of buprenorphine acetate saltis characterized by an XRPD pattern, obtained using CuKα radiation,comprising peaks at 20 angles substantially equivalent to at least thepeaks at 8.77, 10.31, 16.21, 18.47, and 18.70, and having at least oneadditional peak at a 20 angle substantially equivalent to at least oneof the peaks at 6.38, 11.93, or 19.40. In some embodiments, thecrystalline form of buprenorphine acetate salt is characterized by anXRPD pattern, obtained using CuKα radiation, comprising peaks at 20angles substantially equivalent to at least the peaks at 8.77, 10.31,16.21, 18.47, and 18.70, and having at least two additional peaks at a20 angle substantially equivalent to at least two of the peaks at 6.38,11.93, or 19.40. In some embodiments, the crystalline form ofbuprenorphine acetate salt is characterized by an XRPD pattern, obtainedusing CuKα radiation, comprising peaks at 20 angles substantiallyequivalent to at least the peaks at 6.38, 8.77, 10.31, 11.93, 16.21,18.47, 18.70, and 19.40.

It will be appreciated that different equipment and/or conditions canresult in slightly different XRPD data being generated. For example,there can be variations in the location and/or relative intensities ofthe peaks. Particularly, the intensities of XRPD peaks can vary as aresult of particle size and shape because of the effects of the packingof the crystalline particles into XRPD mounts. Such packing effects areknown in the art and are often referred to as the “preferredorientation” effect. Preferred orientation in samples influences theintensities of various XRPD peaks so that some are more intense andothers are less intense, compared to that which would be expected from acompletely random sample. XRPD intensity variations can occur because ofdiffering particle size and shape. The art also recognizes that theposition of XRPD peaks is affected by the precise height at which thesample sits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample can also have asmall effect. Thus, the XRPD data presented are not to be taken asabsolute values.

In some embodiments, the crystalline form of buprenorphine acetate saltis characterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 4, obtained using CuKα radiation. A first XRPDpeak is considered to have the same ° 20 angle as a second XRPD peak,i.e., be substantially equivalent to, if the first peak has a ° 20 anglewithin ±0.2° of the second peak.

In some embodiments, the crystalline form of buprenorphine acetate saltis characterized by a differential scanning calorimetry (“DSC”)transition profile. The DSC measures the heat flow from a sample as afunction of temperature, with a typical heating rate (i.e., temperatechange) of about 10° C./min. In some embodiments, the crystalline formof buprenorphine acetate salt is characterized by a transition with atleast one peak position at from about 50° C. to about 180° C., or fromabout 50° C. to about 140° C., or from about 80° C. to about 130° C., orfrom about 90° C. to about 130° C., or from about 90° C. to about 120°C., or from about 95° C. to about 115° C., as measured by a heat flowdifferential scanning calorimeter at a heating rate of about 10° C. perminute.

In some embodiments, the crystalline form of the buprenorphine acetatesalt is characterized by a transition having a peak position at fromabout 217° C. to about 225° C., or from about 218° C. to about 223° C.,or from about 219° C. to about 223° C., as measured by a heat flowdifferential scanning calorimeter at a heating rate of about 10° C. perminute.

In some embodiments, the crystalline form of the buprenorphine acetatesalt is characterized by a transition with at least one peak position atfrom about 50° C. to about 180° C., or from about 50° C. to about 140°C., or from about 80° C. to about 130° C., or from about 90° C. to about130° C., or from about 90° C. to about 120° C., or from about 95° C. toabout 115° C. and by another transition having a peak position at fromabout 210° C. to about 225° C., or from about 217° C. to about 225° C.,or from about 218° C. to about 223° C., or from about 219° C. to about223° C., as measured by a heat flow differential scanning calorimeter ata heating rate of about 10° C. per minute.

In some embodiments, the crystalline form of the buprenorphine acetatesalt is characterized by a first transition region (Region 1) with atleast one peak having a peak position at from about 50° C. to about 180°C., and a second transition region (Region 2) having a peak having apeak position at from about 210° C. to about 225° C., as discussed aboveand as measured by a heat flow differential scanning calorimeter at aheating rate of about 10° C. per minute.

In some embodiments, the crystalline form of the buprenorphine acetatesalt is characterized by a DSC profile substantially the same as the DSCprofile shown in FIG. 5, when measured by a heat flow differentialscanning calorimeter at a heating rate of about 10° C. per minute. Insome embodiments, the crystalline form of the buprenorphine acetate saltis characterized by a DSC profile substantially the same as the DSCprofile shown in FIG. 6, when measured by a heat flow differentialscanning calorimeter at a heating rate of about 10° C. per minute.

In some embodiments, the crystalline form of the buprenorphine acetateis characterized by an integral (area under the curve) ratio of thefirst transition region (Region 1) over the second transition region(Region 2), i.e., Region 1/Region 2, of from about 7.0 to about 8.0. Insome embodiments, the approximate integral ratio of Region 1/Region 2for buprenorphine acetate is from about 7.1 to about 7.9. In someembodiments, the approximate integral ratio of Region 1/Region 2 forbuprenorphine acetate is from about 7.1 to about 7.7. In someembodiments, the integral values for the transition regions aredetermined over the temperature range of from about 35° C. to about 180°C. for the first transition region (Region 1) and over the temperaturerange of from about 203° C. to about 233° C. for the second transitionregion (Region 2).

In some embodiments, the crystalline form of buprenorphine acetate saltis characterized by a water content of from about 11.1 wt % to about13.0 wt %, or from about 11.5 wt % to about 12.6 wt %, or from about11.8 wt % to about 12.5 wt %, or from about 12.0 wt % to about 12.3 wt%, as measured by Karl Fischer titration. In some embodiments, thecrystalline form of buprenorphine acetate salt is characterized by awater content of about 12.3 wt %, about 12.25 wt %, or about 12.0 wt %.In some embodiments, the foregoing water content is for thebuprenorphine acetate tetrahydrate, i.e., the compound of formula (1b).

In some embodiments, the crystalline form of buprenorphine acetate saltis characterized by one or more of the following:

(1) at least one of the XRPD peaks 20 shown in Table 1;

(2) an XRPD pattern substantially similar to FIG. 4;

(3) a DSC profile substantially similar to FIG. 5 or FIG. 6;

(4) a DSC integral ratio of transition Region 1/Region 2 of from about7.0 to about 8.0; and

(5) a water content of from about 11.1 wt % to about 13.0 wt %.

In some embodiments, the crystalline form of buprenorphine acetate saltis characterized by two, three, four, or all of the features (1) to (5)above.

In some embodiments, the crystalline form of the buprenorphine acetatesalt is characterized as a monoclinic crystal, such as described in thecrystal characterization data presented in Table 4 herein below. In someembodiments, the crystalline form is characterized by monoclinic spacegroup P2₁. In some embodiments, the crystalline form has unit cellparameters of a=10.5±0.5 Å, b=10.9±0.5 Å, and c=14.4±0.5 Å. In someembodiments, the crystalline form has unit cell parameters ofa=10.52±0.05 Å, b=10.92±0.05 Å, and c=14.44±0.05 Å. In some embodiments,the crystalline form of the buprenorphine acetate salt is a monocliniccrystal of space group P2₁ having unit cell parameters of a=10.5±0.5 Å,b=10.9±0.5 Å, and c=14.4±0.5 Å. In some embodiments, the crystallineform of the buprenorphine acetate salt is a monoclinic crystal of spacegroup P2₁ having unit cell parameters of a=10.52±0.05 Å, b=10.92±0.05 Å,and c=14.44±0.05 Å.

In some embodiments, the crystalline form of buprenorphine acetate hasthe same or equivalent fractional atomic coordinates (×10⁴) andequivalent isotropic displacement parameters (Å²×10³) set forth in Table5.

In some embodiments, the buprenorphine acetate and its polymorphic formsexhibit high stability. In some embodiments, the buprenorphine acetateand its polymorphic forms retain about 95.0 area % or greater purity,about 96.0 area % or greater purity, about 97.0 area % or greaterpurity, about 98.0 area % or greater purity, about 98.5 area % orgreater purity, about 99.0 area % or greater purity, about 99.1 area %or greater purity, about 99.2 area % or greater purity, about 99.3 area% or greater purity, about 99.4 area % or greater purity, about 99.5area % or greater purity, about 99.6 area % or greater purity, about99.7 area % or greater purity, about 99.8 area % or greater purity, orabout 99.9 area % or greater purity under long term stability conditions(i.e., 25° C. at 65% relative humidity). In some embodiments, thebuprenorphine acetate and its polymorphic forms retain about 95.0 area %or greater purity, about 96.0 area % or greater purity, about 97.0 area% or greater purity, about 98.0 area % or greater purity, about 98.5area % or greater purity, about 99.0 area % or greater purity, about99.1 area % or greater purity, about 99.2 area % or greater purity,about 99.3 area % or greater purity, about 99.4 area % or greaterpurity, about 99.5 area % or greater purity, about 99.6 area % orgreater purity, about 99.7 area % or greater purity, about 99.8 area %or greater purity, or about 99.9 area % or greater purity underaccelerated stability conditions (i.e., 40° C. at 75% relative humidity)(See Example 7 below for the method of determining the area % impurityunder stability testing conditions). Generally, to be considered asunaffected by moisture, the ICH Guidelines and US Pharmacopeia and EMAMonographs require that a drug compound should be stable under theaccelerated storage condition of 40° C.±2° C. at 75% RH±5%(“RH”=relative humidity) for a minimum time period of 6 months andstable under long term (i.e., for a minimum time period of 12 months)storage conditions of 25° C.±2° C. at 60% RH±5% or 30° C.±2° C. at 65%RH±5%.

In some embodiments, buprenorphine acetate and its polymorphic formsexhibit high photostability. In some embodiments, the buprenorphineacetate and its polymorphic forms retain about 99.0 area % or greaterpurity, about 99.1 area % or greater purity, about 99.2 area % orgreater purity, about 99.3 area % or greater purity, about 99.4 area %or greater purity, about 99.5 area % or greater purity, about 99.6 area% or greater purity, about 99.7 area % or greater purity, about 99.8area % or greater purity, or about 99.9 area % or greater purity whenexposed to continuous UV light, e.g., UV light from a TL 20W/12RS UVbulb (Philips Lighting) at 21.9 W/m², for up to 3 months. In someembodiments, the buprenorphine acetate and its polymorphic forms retainabout 99.0 area % or greater purity, about 99.1 area % or greaterpurity, about 99.2 area % or greater purity, about 99.3 area % orgreater purity, about 99.4 area % or greater purity, about 99.5 area %or greater purity, about 99.6 area % or greater purity, about 99.7 area% or greater purity, about 99.8 area % or greater purity, or about 99.9area % or greater purity when exposed to visible light, e.g., visiblelight from a F24T12/CW/HO fluorescent bulb (Philips Lighting) at 27 Klux for up to 3 months.

It has been discovered that the identity of the impurities present in,or absent from, the buprenorphine acetate of the disclosure are the sameas the identity of the impurities present in, or absent from, thebuprenorphine free base prepared from that buprenorphine acetate. Forexample, if a compound of formula (12) (see Section 4.3) is present inthe buprenorphine acetate of the disclosure while a compound of formula(18) (see Section 4.3) is absent therefrom, then the compound of formula(12) will be present in the buprenorphine free base prepared from thatbuprenorphine acetate while the compound of formula (18) will be absenttherefrom. It has also been discovered that the quantity of eachimpurity present in the buprenorphine acetate of the disclosure is aboutthe same as the quantity of that impurity present in the buprenorphinefree base prepared from that buprenorphine acetate. For example, if0.080% of the compound of formula (12) is present in the buprenorphineacetate of the disclosure, then about 0.080% (±20%, i.e., from about0.064% to about 0.096%) of the compound of formula (12) will be presentin the buprenorphine free base prepared from that buprenorphine acetate.Thus, characterization of the identity and quantity of an impurity orimpurities in the buprenorphine acetate of the disclosure also generallyprovides the impurity characterization for the buprenorphine free baseprepared from that buprenorphine acetate, and vice versa.

4.3 Methods for Preparing Buprenorphine Acetate Salt, and BuprenorphineAcetate Made by the Methods

In another aspect, the disclosure provides methods for preparing highlypure buprenorphine acetate. In a surprising discovery of the disclosure,the acetate salt of buprenorphine, prepared in the procedures describedherein below, provides an intermediate through which very high puritybuprenorphine can be attained under relatively mild conditions with veryhigh yields, the buprenorphine being substantially free of impurities.In some embodiments, the buprenorphine acetate is essentially pure. Insome embodiments, the buprenorphine acetate is essentially more pure. Insome embodiments, the buprenorphine acetate is essentially free ofimpurities. In some embodiments, a method for preparing the acetate saltof buprenorphine comprises the steps of:

(a) contacting buprenorphine free base with a solution comprising aceticacid in a dissolution vessel to form an admixture, where the admixtureis at a temperature of from about 40° C. to about 80° C.;

(b) optionally filtering the admixture of step (a);

(c) adding an agent to the admixture produced in step (a) or (b) toprecipitate the acetate salt of buprenorphine; and

(d) isolating the acetate salt of buprenorphine precipitated in step(c).

In some embodiments, in step (a) of the method the buprenorphine freebase is contacted with from about 2.0 mass equivalents to about 6.0 massequivalents, or from about 3.0 mass equivalents to about 5.0 massequivalents, or from about 3.5 mass equivalents to about 4.5 massequivalents of the acetic acid solution relative to the starting mass ofthe buprenorphine free base.

In some embodiments, the acetic acid solution used in step (a) is anaqueous acetic acid solution. The aqueous acetic acid solution containsat least a sufficient concentration of acetic acid to form,stoichiometrically, the acetate salt of all of the buprenorphine freebase starting material. In some embodiments, the acetic acid in theaqueous solution is present at from about 40 wt % to about 70 wt %, orfrom about 45 wt % to about 60 wt %, or from about 45 wt % to about 55wt %, or from about 47 wt % to about 55 wt %, or from about 49 wt % toabout 53 wt % relative to the weight of the aqueous solution.

In some embodiments, in step (a) of the method the acetic acid solutionsupplied to the dissolution vessel is at a temperature of from about 40°C. to about 80° C., or from about 45° C. to about 75° C., or from about50° C. to about 70° C., or from about 55° C. to about 65° C. In someembodiments, in step (a) of the method the acetic acid solution is anaqueous acetic acid solution and is at a temperature of from about 40°C. to about 80° C., or from about 45° C. to about 75° C., or from about50° C. to about 70° C., or from about 55° C. to about 65° C. whensupplied to the dissolution vessel.

In some embodiments, in step (a) of the method the admixture is at atemperature of from about 40° C. to about 80° C., or from about 45° C.to about 75° C., or from about 50° C. to about 70° C., or from about 55°C. to about 65° C. for a period of time such that at least a substantialportion of the buprenorphine free base has dissolved. In someembodiments, the admixture is heated to a temperature in the specifiedtemperature range, or in some embodiments, the solution at a temperaturein the specified temperature range is added to the buprenorphine freebase to prepare the admixture. In reference to a substantial portion ofthe buprenorphine free base having dissolved, in one embodiment asubstantial portion of the buprenorphine free base has dissolved when atleast about 30 wt % of the buprenorphine free base has dissolved. Inother embodiments, a substantial portion of the buprenorphine free basehas dissolved when at least about 50 wt %, at least about 60 wt %, or atleast about 75 wt % of the buprenorphine free base has dissolved. Thequantity corresponding to “substantial portion of the buprenorphine freebase has dissolved” can be determined from the yield of the resultingbuprenorphine acetate salt as follows: if the determined yield ofbuprenorphine acetate salt remains relatively constant (within 5%) uponaddition of an even greater quantity of buprenorphine free base then asubstantial portion of the buprenorphine free base had dissolved beforethe addition of the even greater quantity of buprenorphine free base. Insome embodiments, the admixture of step (a) is agitated to acceleratedissolution of the buprenorphine free base. Agitation of the admixturecan be achieved by a variety of techniques, including stirring,sonication, or shaking.

In some embodiments, the admixture of step (a) can optionally befiltered according to step (b) by using, e.g., a filtration apparatus.The filtration can be done with a filtration apparatus at suitabletemperatures, including at a temperature of from about 40° C. to about80° C., or from about 45° C. to about 75° C., or from about 50° C. toabout 70° C., or from about 55° C. to about 65° C. In some embodiments,in step (b) the admixture of step (a) added to the filtration apparatusis at a temperature of from about 40° C. to about 80° C. or at atemperature of from about 45° C. to about 75° C. In some embodiments, anadditional volume of an acetic acid solution is used to rinse thedissolution vessel and the filtration apparatus. This additional volumeof the acetic acid solution can be from about 0.1 mass equivalents toabout 2.0 mass equivalents, or from about 0.1 mass equivalents to about1.1 mass equivalents, or from about 0.2 mass equivalents to about 1.5mass equivalents, or from about 0.5 mass equivalents to about 1.1 massequivalents, or from about 0.5 mass equivalents to about 1.0 massequivalent, or from about 0.3 mass equivalents to about 0.5 massequivalents relative to the starting mass of free base in step (a).

In some embodiments, the additional volume of the acetic acid solutionis an aqueous acetic acid solution. In some embodiments, the aqueoussolution of acetic acid can have an amount of acetic acid of from about40 wt % to about 70 wt %, or from about 45 wt % to about 60 wt %, orfrom about 45 wt % to about 55 wt %, or from about 47 wt % to about 55wt %, or from about 49 wt % to about 53 wt % relative to the weight ofthe aqueous solution.

In some embodiments, in step (c) of any of the preceding methods andvariations thereof the agent of step (c) is selected from ananti-solvent, a seed crystal, and combinations thereof.

In some embodiments, the agent of step (c) comprises an anti-solvent.Any anti-solvent suitable for initiating precipitation of the acetatesalt of buprenorphine and achieving the product with a desiredcharacteristic, e.g., a reduced product impurity level, can be used. Insome embodiments, the anti-solvent comprises water. In some embodiments,from about 0.2 mass equivalents to about 8.0 mass equivalents, or fromabout 0.5 mass equivalents to about 4.0 mass equivalents, or from about0.5 mass equivalents to about 2.0 mass equivalents, or from about 0.5mass equivalents to about 1.0 mass equivalent, or from about 0.6 massequivalents to about 0.9 mass equivalents, or from about 0.7 massequivalents to about 0.8 mass equivalents of anti-solvent relative tothe starting mass of free base in step (a) are added to the admixture ofstep (a) or (b). Generally, the anti-solvent is added at a temperaturesufficient to achieve the precipitation of the acetate salt ofbuprenorphine. In some embodiments, the anti-solvent is added at withinabout 10° C. or within about 5° C. of the temperature of the admixtureof step (a) or step (b) above, particularly at from about 45° C. toabout 75° C., or from about 50° C. to about 70° C., or from about 50° C.to about 65° C., or from about 55° C. to about 65° C.

In some embodiments, the anti-solvent is added over a period of fromabout 0.5 hours to about 3.0 hours, or from about 0.5 hours to about 2.5hours, or from about 1.0 hours to about 2.0 hours.

In some embodiments, the anti-solvent is added in a single portion. Inother embodiments, the anti-solvent is added in a plurality of portions,i.e., portion-wise. For example, the anti-solvent can be added in 2, 3,4, 5, 6, 7, 8, 9, 10, or more distinct portions throughout step (c). Theindividual quantities of the anti-solvent in each portion can be thesame or different. Portions of the anti-solvent can be added atwell-defined intervals during step (c). For example, individual portionsof the anti-solvent can be added about every 0.1 hour to 4.0 hours, orabout every 0.5 hours as step (c) progresses. Alternatively, individualportions of the anti-solvent can be added at times during step (c) whenthe rate of formation of the buprenorphine acetate salt decreases.

In other embodiments, the anti-solvent is added continuously during step(c). In another embodiment, continuous addition is achieved by slowlydropping the anti-solvent from an addition funnel into the admixture. Inanother embodiment, continuous addition is achieved by filling ahypodermic syringe equipped with a mechanically-driven plunger with theanti-solvent and adding the anti-solvent through a hypodermic needleinto the admixture. In another embodiment, continuous addition isachieved by adding the anti-solvent into the admixture with a mechanicalpump.

Methods for carrying out portion-wise and continuous addition of ananti-solvent are known in the art. For example, U.S. Pat. Nos.2,191,786, 2,583,420, 3,355,486, 3,749,646, 4,217,787, 6,486,692, and6,994,827, hereby incorporated by reference, disclose vessels in whichone reagent is added incrementally to an admixture. Incremental additionis known in the art as the metering-in over a finite period of time, incontrast with the addition of the total anti-solvent into the vessel atonce. The term incremental addition includes addition using a continuousstream, addition using a variable stream, addition intermittently usingseparate portions, and other related methods. See U.S. Pat. No.4,217,287 (col. 2, lines 56-62).

In some embodiments, the agent of step (c) comprises a seed crystal. Inparticular, the seed crystal comprises buprenorphine acetate salt. Theseed crystal can be added in a sufficient amount to initiateprecipitation of the buprenorphine acetate salt from solution in theadmixture. In some embodiments, from about 0.1 wt % to about 10 wt %, orfrom about 0.1 wt % to about 9 wt %, or from about 0.1 wt % to about 8wt %, or from about 0.1 wt % to about 7 wt %, or from about 0.1 wt % toabout 6 wt %, or from about 0.1 wt % to about 5 wt %, or from about 0.1wt % to about 4 wt %, or from about 0.1 wt % to about 3 wt %, or fromabout 0.1 wt % to about 2 wt %, or from about 0.1 wt % to about 1 wt %,or from about 0.2 wt % to about 0.8 wt %, or from about 0.3 wt % toabout 0.7 wt %, or from about 0.4 wt % to about 0.6 wt %, or from about0.2 wt % to about 0.5 wt % of seed crystal is added to the admixture ofstep (a) or (b) relative to the starting mass of free base in step (a).In some embodiments, from about 0.2 wt % to about 9 wt %, or from about0.5 wt % to about 9 wt %, or from about 1 wt % to about 5 wt %, or fromabout 2 wt % to about 4 wt % of seed crystal is added to the admixtureof step (a) or (b) relative to the starting mass of free base in step(a).

In some embodiments, the seed crystal is added at a suitable temperaturethat initiates precipitation of the acetate salt. In some embodiments,the admixture of step (a) or (b) is at a temperature of from about 40°C. to about 80° C., or from about 45° C. to about 75° C., or from about50° C. to about 70° C., or from about 50° C. to about 65° C., or fromabout 53° C. to about 63° C., or from about 56° C. to about 63° C., orfrom about 58° C. to about 62° C., or from about 59° C. to about 61° C.when the seed crystal is added.

In some embodiments, in step (c) the agent for precipitating thebuprenorphine acetate salt comprises a combination of both ananti-solvent and a seed crystal. In some embodiments, a first amount ofanti-solvent is added, before, after, or concurrently with the additionof a seed crystal. This may further optionally be followed by theaddition of a second amount of anti-solvent. In some embodiments, thefirst amount of anti-solvent is from about 0.2 mass equivalents to about2.0 mass equivalents, or from about 0.35 mass equivalents to about 0.80mass equivalents, or from about 0.5 mass equivalents to about 1.0 massequivalent, or from about 0.6 mass equivalents to about 0.9 massequivalents, or from about 0.65 mass equivalents to about 0.75 massequivalents relative to the starting mass of free base in step (a). Insome embodiments, when a seed crystal is used in combination with ananti-solvent, from about 0.1 wt % to about 10 wt %, or from about 0.1 wt% to about 9 wt %, or from about 0.1 wt % to about 8 wt %, or from about0.1 wt % to about 7 wt %, or from about 0.1 wt % to about 6 wt %, orfrom about 0.1 wt % to about 5 wt %, or from about 0.1 wt % to about 4wt %, or from about 0.1 wt % to about 3 wt %, or from about 0.1 wt % toabout 2 wt %, or from about 0.1 wt % to about 1 wt %, or from about 0.2wt % to about 0.8 wt %, or from about 0.3 wt % to about 0.7 wt %, orfrom about 0.4 wt % to about 0.6 wt %, or from about 0.2 wt % to about0.5 wt % of seed crystal is added relative to the starting mass of freebase in step (a). In some embodiments, the second, optional amount ofanti-solvent is from about 1.0 mass equivalent to about 8.0 massequivalents, or from about 1.0 mass equivalent to about 6.5 massequivalents, or from about 4.0 mass equivalents to about 6.5 massequivalents, or from about 5.0 mass equivalents to about 6.5 massequivalents, or from about 5.6 mass equivalents to about 6.1 massequivalents, or from about 5.75 mass equivalents to about 6.00 massequivalents, or from about 5.8 mass equivalents to about 6.0 massequivalents relative to the starting mass of free base in step (a). Insome embodiments, the temperature of the admixture during addition ofthe second, optional amount of anti-solvent is about the same as thetemperature of the admixture in step (a). In some embodiments, thetemperature of the admixture during addition of the second, optionalamount of anti-solvent is different from the temperature of theadmixture in step (a). In some embodiments, the temperature of theadmixture during addition of the second, optional amount of anti-solventis about the same as the temperature of the admixture during theaddition of the first amount of anti-solvent. In some embodiments, thetemperature of the admixture during addition of the second, optionalamount of anti-solvent is different from the temperature of theadmixture during the addition of the first amount of anti-solvent.

In some embodiments, when initiating precipitation with a seed crystal,the admixture can be held at the admixture's temperature when the seedwas added for up to 48 hrs, up to 36 hrs, up to 24 hrs, up to 12 hrs, upto 6 hrs, up to 5 hrs, up to 4 hrs, up to 3 hrs, up to 2 hrs, up to 1hr, or up to 0.5 hrs.

In some embodiments, for any of the preceding methods, the method canfurther comprise cooling the admixture of step (c), following additionof the agent and prior to isolating the acetate salt of buprenorphine instep (d), to a temperature of about 30° C. or lower, about 25° C. orlower, about 20° C. or lower, about 15° C. or lower, or about 10° C. orlower. In some embodiments, the solution is cooled to a temperature offrom about 5° C. to about 30° C., or from about 5° C. to about 25° C.,or from about 5° C. to about 20° C., or from about 10° C. to about 20°C.

In some embodiments, for any of the preceding methods, the method canfurther comprise adding a co-solvent to the admixture following theprecipitation of step (c) but prior to the isolation in step (d). Insome embodiments, any co-solvent that provides or enhances the desirableproperties of the product, e.g., to reduce a product impurity level, orprocess, e.g., to reduce foaming, can be used. In some embodiments, theco-solvent is an alcohol, for example, selected from methanol, ethanol,isopropyl alcohol (“IPA”), and combinations thereof. In someembodiments, the co-solvent is IPA.

In some embodiments, the amount of co-solvent added is from about 0.6mass equivalents to about 0.8 mass equivalents, or from about 0.75 massequivalents to about 0.65 mass equivalents, or from about 0.73 massequivalents to about 0.67 mass equivalents relative to the starting massof free base in step (a). In some embodiments, the temperature ofco-solvent being added is from about 50° C. to about 70° C., or fromabout 52° C. to about 68° C., or from about 55° C. to about 65° C.

In some embodiments, following the addition of co-solvent and prior toisolating the acetate salt of buprenorphine in step (d), the method canfurther comprise cooling the admixture to a temperature of about 30° C.or lower, about 25° C. or lower, about 20° C. or lower, about 15° C. orlower, or about 10° C. or lower. In some embodiments, the solution iscooled to a temperature of from about 5° C. to about 30° C., or fromabout 5° C. to about 25° C., or from about 5° C. to about 20° C., orfrom about 10° C. to about 20° C. In some embodiments, the cooling rateis from about 1° C./hr to about 20° C./hr, or from about 4° C./hr toabout 15° C./hr, or from about 5° C./hr to about 12° C./hr, or fromabout 6° C./hr to about 10° C./hr.

Following the precipitation of the buprenorphine acetate salt in step(c), the method further comprises step (d) of isolating thebuprenorphine acetate salt. In some embodiments, the isolation in step(d) is accomplished by filtration, centrifugation, trituration, ordecantation.

In some embodiments, the method further comprises slurrying thebuprenorphine acetate salt obtained from step (d) using a slurryingsolution. In some embodiments, the slurrying solution comprises analcohol, such as IPA, or water and alcohol, such as water and IPA. Theslurry can be filtered to provide a preparation of buprenorphine acetatesalt.

As discussed above, the buprenorphine acetate salt prepared by any ofthe methods described above, and polymorphic forms thereof, areessentially free of impurities, and thus in some embodiments, result inessentially pure buprenorphine acetate salt. Some impurities producedduring the synthesis of buprenorphine have similar chemical propertiesto buprenorphine, which tends to make purification of the final productdifficult. As noted above, it has been discovered that buprenorphineacetate salt, and in particular the buprenorphine acetate salt preparedby the methods disclosed herein, has a lower level of impurities, and insome embodiments, is essentially free of impurities. Without being boundby theory, it is believed that the reduction in impurities occurs duringthe precipitation of crystalline buprenorphine acetate salt; theundesirable impurities are believed to remain in solution in theadmixture of step (c) after isolation of the buprenorphine acetate salt.Accordingly, in another aspect the disclosure provides buprenorphineacetate salts prepared by any of the methods described herein, andparticularly the compound of formula (1b), each having an advantageouslyimproved impurity profile.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (10):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (11):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (12):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (13):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (14):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (15):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (16):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (17):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (18):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, comprises about 0.10 wt % or less, about 0.09wt % or less, about 0.08 wt % or less, about 0.07 wt % or less, about0.06 wt % or less, or about 0.05 wt % or less of an impurity representedby the compound of formula (19):

or a salt thereof.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, and thecrystalline forms thereof, is essentially free of impurities. In someembodiments, the total amount of impurities, including the combinedlevel of impurities of the compounds of formulae (10), (11), (12), (13),(14), and (15), is about 0.70 wt % or less, about 0.65 wt % or less,about 0.60 wt % or less, about 0.55 wt % or less, about 0.50 wt % orless, about 0.45 wt % or less, about 0.40 wt % or less, about 0.35 wt %or less, about 0.30 wt % or less, about 0.25 wt % or less, about 0.20 wt% or less, about 0.15 wt % or less, or about 0.10 wt % or less.

In some embodiments, the buprenorphine acetate salt preparation of thedisclosure, including the anhydrates, solvates, hydrates, andcrystalline forms thereof, is essentially free of impurities. In someembodiments, the total amount of impurities, including the combinedlevel of impurities of the compounds of formulae (10), (11), (12), (13),(14), (15), (16), (17), (18), and (19), is about 0.70 wt % or less,about 0.65 wt % or less, about 0.60 wt % or less, about 0.55 wt % orless, about 0.50 wt % or less, about 0.45 wt % or less, about 0.40 wt %or less, about 0.35 wt % or less, about 0.30 wt % or less, about 0.25 wt% or less, about 0.20 wt % or less, about 0.15 wt % or less, or about0.10 wt % or less.

4.4 Buprenorphine Free Base, Buprenorphine Salts, and Methods forPreparing the Same

As discussed above, the buprenorphine acetate salts, and the solvates,hydrates, anhydrates, and crystalline forms thereof, allow separation ofimpurities present in current preparations of buprenorphine, and thusprovide a synthetic intermediate for preparing buprenorphine, includingits free base and other salt forms, of increased purity. By using themethods of the disclosure, buprenorphine, including its free base, saltforms, solvates, hydrates, anhydrates, and crystalline forms can beprepared essentially free of impurities.

Accordingly, in a further aspect, the disclosure provides a method forpreparing buprenorphine free base, the method comprising treating anacetate salt of buprenorphine under sufficient conditions to remove theacetic acid counterion, thereby providing the buprenorphine free base(and acetic acid). In some embodiments, the treatment step removes theacetate counterion sufficiently to yield an essentially purebuprenorphine free base. In some embodiments, the amount of acetateremaining in the buprenorphine free base preparation is less than about0.10 wt %, less than about 0.09 wt %, less than about 0.08 wt %, lessthan about 0.07 wt %, less than about 0.06 wt %, or less than about 0.05wt %.

A first method for preparing buprenorphine free base from an acetatesalt of buprenorphine, e.g., from buprenorphine acetate tetrahydrate,comprises the steps of:

(a) contacting an acetate salt of buprenorphine with a solution and abasic material to form an admixture;

(b) agitating the admixture of step (a) at a temperature of from about20° C. to about 90° C. to provide buprenorphine free base;

(c) isolating the buprenorphine free base of step (b); and

(d) optionally repeating steps (a) through (c) one or more times.

In some embodiments of this first method for preparing buprenorphinefree base from an acetate salt of buprenorphine, in step (a), theacetate salt of buprenorphine is contacted with at least about the samemass (i.e., about 1 mass equivalent) of the solution relative to thestarting mass of acetate salt in step (a). In some embodiments, in step(a), the acetate salt of buprenorphine is contacted with from about 1.0mass equivalent to about 6.0 mass equivalents, or from about 2.0 massequivalents to about 5.0 mass equivalents, or from about 2.0 massequivalents to about 4.0 mass equivalents, or from about 3.0 massequivalents to about 4.0 mass equivalents of the solution relative tothe starting mass of acetate salt in step (a). The acetate salt ofbuprenorphine dissolves at least partially in the solution; however, thebuprenorphine free base is relatively insoluble therein and canprecipitate. In some embodiments, the solution of step (a) compriseswater and an alcohol. In some embodiments, the water and alcoholsolution comprises from about 30 wt % to about 70 wt % alcohol in water,or from about 40 wt % to about 60 wt % alcohol in water, or from about50 wt % to about 60 wt % alcohol in water. In some embodiments, thealcohol is selected from methanol, ethanol, IPA, and combinationsthereof. In some embodiments, the alcohol is IPA. In some embodiments,the water and alcohol solution comprises from about 30 wt % to about 70wt % IPA in water, or from about 40 wt % to about 60 wt % IPA in water,or from about 50 wt % to about 60 wt % IPA in water.

In some embodiments of this first method for preparing buprenorphinefree base from an acetate salt of buprenorphine, the basic material usedin step (a) can be any base suitable for preparing buprenorphine freebase. In some embodiments, the basic material is selected from ahydroxide, carbonate, alkoxide, hydride, phosphate, borate (such asborax), oxide (such as CaO), cyanide (such as KCN), silicate (such assodium metasilicate), amine (such as triethylamine, pyridine, or4-dimethylaminopyridine), and the like, and combinations thereof. Insome embodiments, the basic material comprises a hydroxide. In someembodiments, the basic material comprises ammonium hydroxide. In someembodiments, the basic material is aqueous ammonium hydroxide.

In some embodiments, the acetate salt of buprenorphine is contacted withfrom about 0.5 molar equivalents to about 20 molar equivalents, or fromabout 1 molar equivalent to about 20 molar equivalents, or from about 1molar equivalent to about 10 molar equivalents, of basic materialrelative to starting moles of the acetate salt of buprenorphine in step(a).

In some embodiments, in step (b) agitating the admixture can be done byany appropriate method, such as by shaking, stirring, or sonicating theadmixture. In some embodiments, in step (b), the admixture is agitatedfor a sufficient time to remove the acetic acid counterion. In someembodiments, the admixture of step (a) is agitated in step (b) fromabout 1 hr to about 36 hrs, or from about 1 hr to about 24 hrs, or fromabout 2 hrs to about 20 hrs, or from about 2 hrs to about 8 hrs, or fromabout 3 hrs to about 7 hrs, or from about 4 hrs to about 6 hrs. In someembodiments, in step (b) the admixture is agitated at a temperature offrom about 25° C. to about 90° C., or from about 25° C. to about 60° C.,or from about 30° C. to about 45° C.

In this first method for preparing buprenorphine free base from anacetate salt of buprenorphine, the free base formed in step (b) isisolated in step (c), for example, by precipitation. Any suitablemethods for isolating the buprenorphine free base can be used. In someembodiments, the isolating in step (c) is accomplished by filtration orby centrifugation to obtain the isolated precipitate.

In some embodiments, the method for preparing buprenorphine free basefrom an acetate salt of buprenorphine optionally further comprises step(d), i.e., repeating steps (a) through (c) one or more times. In someembodiments of step (d), steps (a) through (c) are repeated once, twice,thrice, or at least thrice.

In some embodiments, the free base isolated in step (c) can besubsequently processed. Thus, in some embodiments, the method forpreparing buprenorphine free base from an acetate salt of buprenorphinecan further comprise a step of slurrying the isolated solid product ofstep (c) with a slurrying solution. In some embodiments, the slurryingsolution comprises a water and alcohol mixture. In some embodiments, theslurrying solution comprises IPA in water, where the alcohol is presentat from about 5 wt % to about 40 wt %, or from about 5 wt % to about 30wt %, or from about 10 wt % to about 30 wt %. The free base can then beisolated from the slurry, such as by filtration or by centrifugation. Insome embodiments, the slurrying temperature is from about 5° C. to about40° C., or from about 10° C. to about 35° C., or from about 15° C. toabout 35° C.

In some embodiments of this first method, acetic acid in the final freebase preparation of buprenorphine is present at less than about 0.7 wt%, less than about 0.5 wt %, less than about 0.3 wt %, less than about0.2 wt %, or less than about 0.1 wt % after the first method is carriedout.

In another aspect, the disclosure provides the buprenorphine free baseprepared by the first method, or by any variations thereof describedabove. In some embodiments, the buprenorphine free base prepared by thefirst method is essentially free of impurities.

In some embodiments, the buprenorphine free base prepared by the firstmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (10):

In some embodiments, the buprenorphine free base prepared by the firstmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (11):

In some embodiments, the buprenorphine free base prepared by the firstmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (12):

In some embodiments, the buprenorphine free base prepared by the firstmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (13):

In some embodiments, the buprenorphine free base prepared by the firstmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (14):

In some embodiments, the buprenorphine free base prepared by the firstmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (15):

In some embodiments, for the free base preparation of buprenorphineprepared by the first method, the combined level of impurities of thecompounds of formulae (10), (11), (12), (13), (14), and (15) is about0.70 wt % or less, about 0.65 wt % or less, about 0.60 wt % or less,about 0.55 wt % or less, about 0.50 wt % or less, about 0.45 wt % orless, about 0.40 wt % or less, about 0.35 wt % or less, about 0.30 wt %or less, about 0.25 wt % or less, or about 0.20 wt % or less.

In some embodiments, for the free base preparation of buprenorphineprepared by the first method, the combined level of impurities of thecompounds of formulae (10), (11), (12), (13), (14), and (15), and anyother impurity or impurities not specifically identified herein, isabout 0.75 wt % or less, about 0.70 wt % or less, about 0.65 wt % orless, about 0.60 wt % or less, about 0.55 wt % or less, about 0.50 wt %or less, about 0.45 wt % or less, about 0.40 wt % or less, about 0.35 wt% or less, about 0.30 wt % or less, about 0.25 wt % or less, or about0.20 wt % or less.

Alternatively, the buprenorphine free base can be prepared from anacetate salt of buprenorphine by removing the acetic acid counterion bymethods such as by heating, evaporating under about atmosphericpressure, evaporating under sub-atmospheric pressure, or any combinationthereof.

Accordingly, a second method for preparing buprenorphine free base froman acetate salt of buprenorphine, e.g., from buprenorphine acetatetetrahydrate, comprises treating an acetate salt of buprenorphine at apressure, temperature and for a time sufficient to remove the aceticacid and water, thereby providing the buprenorphine free base. In someembodiments, the treating is at a temperature of at least about 30° C.over a period of time sufficient to remove the acetic acid and water. Insome embodiments, such treating is done for at least 1 hr.

In some embodiments of this second method, the acetate salt ofbuprenorphine is treated under sub-atmospheric pressure, for example, ata pressure of from about 50 Torr to about 250 Torr, or from about 75Torr to about 225 Torr, or from about 100 Torr to about 200 Torr, orfrom about 125 Torr to about 175 Torr. In some embodiments, suchtreating is done at about 150 Torr.

In some embodiments of this second method, the acetate salt ofbuprenorphine is treated under about atmospheric pressure, for example,at a pressure of from about 620 Torr to about 780 Torr, or from about670 Torr to about 780 Torr, or from about 700 Torr to about 780 Torr, orfrom about 740 Torr to about 780 Torr, or from about 750 Torr to about770 Torr, or from about 755 Torr to about 765 Torr. In some embodiments,such treating is done at an atmospheric pressure of about 760 Torr.

In some embodiments of this second method for preparing buprenorphinefree base from an acetate salt of buprenorphine, the acetate salt ofbuprenorphine is treated at a temperature of at least about 45° C., atleast about 50° C., or at least about 65° C. In some embodiments of thissecond method for preparing buprenorphine free base from an acetate saltof buprenorphine, the treatment temperature is from about 50° C. toabout 110° C., or from about 50° C. to about 105° C., or from about 60°C. to about 100° C., or from about 65° C. to about 100° C.

In some embodiments of this second method, the heating at the treatmenttemperature lasts for at least about 5 hrs, for at least about 6 hrs,for at least about 7 hrs, for at least about 9 hrs, for at least about10 hrs, for at least about 12 hrs, or lasts long enough to formessentially pure buprenorphine free base.

In some embodiments, this second method for preparing buprenorphine freebase from an acetate salt of buprenorphine further comprises slurryingthe free base with a slurrying solution and filtering the solid freebase therefrom. In some embodiments, the slurrying solution compriseswater and an alcohol, as disclosed above for the first method.

In some embodiments of this second method, acetic acid in the final freebase preparation of buprenorphine is present at less than about 0.7 wt%, less than about 0.5 wt %, less than about 0.3 wt %, less than about0.2 wt %, or less than about 0.1 wt %.

In another aspect, the disclosure provides the buprenorphine free baseprepared by the second method, or by any variations thereof describedabove. In some embodiments, the buprenorphine free base prepared by thesecond method is essentially free of impurities.

In some embodiments, the buprenorphine free base prepared by the secondmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (10).

In some embodiments, the buprenorphine free base prepared by the secondmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (11).

In some embodiments, the buprenorphine free base prepared by the secondmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (12).

In some embodiments, the buprenorphine free base prepared by the secondmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (13).

In some embodiments, the buprenorphine free base prepared by the secondmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (14).

In some embodiments, the buprenorphine free base prepared by the secondmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (15).

In some embodiments, for the buprenorphine free base prepared by thesecond method, the combined level of impurities of the compounds offormulae (10), (11), (12), (13), (14), and (15), is about 0.70 wt % orless, about 0.65 wt % or less, about 0.60 wt % or less, about 0.55 wt %or less, about 0.50 wt % or less, about 0.45 wt % or less, about 0.40 wt% or less, about 0.35 wt % or less, about 0.30 wt % or less, about 0.25wt % or less, or about 0.20 wt % or less.

In some embodiments, for the buprenorphine free base prepared by thesecond method, the combined level of impurities of the compounds offormulae (10), (11), (12), (13), (14), and (15), and any other impurityor impurities not specifically identified herein, is about 0.75 wt % orless, about 0.70 wt % or less, about 0.65 wt % or less, about 0.60 wt %or less, about 0.55 wt % or less, about 0.50 wt % or less, about 0.45 wt% or less, about 0.40 wt % or less, about 0.35 wt % or less, about 0.30wt % or less, about 0.25 wt % or less, or about 0.20 wt % or less.

A third method for preparing buprenorphine free base from an acetatesalt of buprenorphine, e.g., from buprenorphine acetate tetrahydrate,comprises the steps of:

(a) dissolving an acetate salt of buprenorphine in a solution to form anadmixture;

(b) optionally filtering the admixture of step (a);

(c) adding a basic material to the admixture in step (a) or (b) to forma second admixture;

(d) adding an anti-solvent to the second admixture produced in step (c)to form a precipitate of the buprenorphine free base; and

(e) isolating the precipitate from step (d).

In some embodiments of this third method for preparing buprenorphinefree base from an acetate salt of buprenorphine, the admixture of step(a) comprises an organic solvent. In some embodiments, the organicsolvent comprises an alcohol. In some embodiments, the organic solventcomprises an alcohol selected from methanol, ethanol and isopropylalcohol. In some embodiments, the alcohol is selected from methanol,ethanol and isopropyl alcohol. In some embodiments, the alcohol is IPA.In some embodiments, the acetate salt of buprenorphine is contacted withat least about 3.0 mass equivalents of the solution relative to thestarting mass of the acetate salt of buprenorphine in step (a).

In some embodiments of this third method, in step (a) the admixture isat a temperature of about 20° C. to about 90° C. In some embodiments, instep (a) the admixture is at a temperature of at least about 20° C., atleast about 40° C., at least about 50° C., at least about 55° C., or atleast about 60° C. The admixture can be at a temperature in thespecified temperature range by various methods, such as by heating theadmixture or by using a solution at a temperature in the specifiedtemperature range. In some embodiments, the admixture is mixed untilsubstantially all of the buprenorphine acetate salt is dissolved in thesolution.

In one embodiment of this third method, substantially all of thebuprenorphine acetate salt is dissolved when at least about 80.0 wt %,at least about 85.0 wt %, at least about 90.0 wt %, at least about 95.0wt %, at least about 98.0 wt %, at least about 99.0 wt %, at least about99.5 wt %, at least about 99.8 wt %, or at least about 99.9 wt % of thebuprenorphine acetate salt is dissolved.

In some embodiments of this third method, the admixture of step (a) isfiltered in step (b). The filtering step (b) removes undissolved solids.

In some embodiments of this third method, in step (c) from about 1.0molar equivalent to about 20.0 molar equivalents, or from about 1.0molar equivalent to about 5.0 molar equivalents, or from about 1.0 molarequivalent to about 2.0 molar equivalents, or from about 1.0 molarequivalent to about 1.2 molar equivalents of basic material are added,relative to the starting number of moles of acetate salt ofbuprenorphine in step (a), to the admixture produced in step (a) or (b).

In some embodiments of this third method, the basic material used instep (c) can be any base suitable for preparing buprenorphine free base.In some embodiments, the basic material is selected from a hydroxide,carbonate, alkoxide, hydride, phosphate, borate (such as borax), oxide(such as CaO), cyanide (such as KCN), silicate (such as sodiummetasilicate), amine (such as triethylamine, pyridine, or4-dimethylaminopyridine), and the like, and combinations thereof. Insome embodiments, the basic material comprises a hydroxide. In someembodiments, the basic material comprises ammonium hydroxide. In someembodiments, the basic material is aqueous ammonium hydroxide.

In some embodiments of this third method, in step (d) at least about 3.0mass equivalents of the anti-solvent, relative to the starting mass ofacetate salt in step (a), are added to the second admixture produced instep (c) so as to provide a precipitate of buprenorphine free base.

In some embodiments of the third method, the anti-solvent consistsessentially of water. In some embodiments, the anti-solvent comprises amixture of water and an alcohol. In some embodiments, in the mixture ofwater and alcohol the alcohol comprises IPA. In some embodiments, in themixture of water and alcohol the alcohol is IPA. In some embodiments,the water and alcohol mixture is from about 95:5 to about 50:50water:alcohol by volume, or from about 90:10 to about 60:40water:alcohol by volume, or from about 85:15 to about 70:30water:alcohol by volume. In some embodiments, the water and alcoholmixture is about 80:20 water:alcohol by volume. In some embodiments, thewater and alcohol mixture is from about 95:5 to about 50:50 water:IPA byvolume, or from about 90:10 to about 60:40 water:IPA by volume, or fromabout 85:15 to about 70:30 water:IPA by volume. In some embodiments, thewater and alcohol mixture is about 80:20 water:IPA by volume.

In some embodiments of the third method, the minimum time for forming aprecipitate of buprenorphine free base in step (d) is about 0.1 hrs. Insome embodiments, the time for forming a precipitate of buprenorphinefree base is from about 0.1 hrs to about 10.0 hrs, or from about 0.1 hrsto about 6.0 hrs, or from about 0.2 hrs to about 5.0 hrs, or from about0.1 hr to about 3.0 hrs, or from about 0.3 hrs to about 3.0 hrs, or fromabout 0.5 hrs to about 3.0 hrs.

Optionally, in some embodiments of the third method, a seed crystal isadded in step (d). In particular, the seed crystal comprisesbuprenorphine free base. The seed crystal can be added in a sufficientamount to initiate precipitation or assist the precipitation of thebuprenorphine free base from the second admixture. In some embodiments,from about 0.1 wt % to about 10 wt %, or from about 0.1 wt % to about 9wt %, or from about 0.1 wt % to about 8 wt %, or from about 0.1 wt % toabout 7 wt %, or from about 0.1 wt % to about 6 wt %, or from about 0.1wt % to about 5 wt %, or from about 0.1 wt % to about 4 wt %, or fromabout 0.1 wt % to about 3 wt %, or from about 0.1 wt % to about 2 wt %,or from about 0.1 wt % to about 1 wt %, or from about 0.2 wt % to about0.8 wt %, or from about 0.3 wt % to about 0.7 wt %, or from about 0.4 wt% to about 0.6 wt %, or from about 0.2 wt % to about 0.5 wt % of seedcrystal is added to the second admixture of step (d) relative to thestarting mass of acetate salt in step (a). In some embodiments, fromabout 0.2 wt % to about 9 wt %, or from about 0.5 wt % to about 9 wt %,or from about 1 wt % to about 5 wt %, or from about 2 wt % to about 4 wt% of seed crystal is added to the second admixture of step (d) relativeto the starting mass of acetate salt in step (a).

In some embodiments, the seed crystal is added at a suitable temperaturethat initiates precipitation of the buprenorphine free base. In someembodiments, the second admixture of step (d) is at a temperature offrom about 40° C. to about 80° C., or from about 45° C. to about 75° C.,or from about 50° C. to about 70° C., or from about 50° C. to about 65°C. when the seed crystal is added.

In some embodiments of this third method, the buprenorphine free baseprepared in step (d) is isolated in step (e). In some embodiments, theisolating is accomplished by filtration. In some embodiments, theisolation in step (e) is performed at a temperature of at least about70° C., at least about 65° C., at least about 60° C., at least about 50°C., or at least about 40° C.

In some embodiments, this third method for preparing buprenorphine freebase further comprises the step of slurrying the free base obtained fromstep (e) with a slurrying solution. In some embodiments, the slurringsolution comprises water or a mixture of water and an alcohol. In someembodiments, the alcohol comprises IPA. Following formation of thisslurry, the free base can be isolated from the slurry, for example, byfiltration or by centrifugation.

In some embodiments of this third method, acetic acid in the final freebase preparation of buprenorphine is present at less than about 0.7 wt%, less than about 0.5 wt %, less than about 0.3 wt %, less than about0.2 wt %, or less than about 0.1 wt %.

In another aspect, the disclosure provides the buprenorphine free baseprepared by the third method, or by any variations thereof describedabove. In some embodiments, the buprenorphine free base prepared by thethird method is essentially free of impurities.

In some embodiments, the buprenorphine free base prepared by the thirdmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (10).

In some embodiments, the buprenorphine free base prepared by the thirdmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (11).

In some embodiments, the buprenorphine free base prepared by the thirdmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (12).

In some embodiments, the buprenorphine free base prepared by the thirdmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (13).

In some embodiments, the buprenorphine free base prepared by the thirdmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (14).

In some embodiments, the buprenorphine free base prepared by the thirdmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (15).

In some embodiments, for the buprenorphine free base prepared by thethird method, the combined level of impurities of the compounds offormulae (10), (11), (12), (13), (14), and (15), is about 0.70 wt % orless, about 0.65 wt % or less, about 0.60 wt % or less, about 0.55 wt %or less, about 0.50 wt % or less, about 0.45 wt % or less, about 0.40 wt% or less, about 0.35 wt % or less, about 0.30 wt % or less, about 0.25wt % or less, or about 0.20 wt % or less.

In some embodiments, for the buprenorphine free base prepared by thethird method, the combined level of impurities of the compounds offormulae (10), (11), (12), (13), (14), and (15), and any other impurityor impurities not specifically identified herein, is about 0.75 wt % orless, about 0.70 wt % or less, about 0.65 wt % or less, about 0.60 wt %or less, about 0.55 wt % or less, about 0.50 wt % or less, about 0.45 wt% or less, about 0.40 wt % or less, about 0.35 wt % or less, about 0.30wt % or less, about 0.25 wt % or less, or about 0.20 wt % or less.

A fourth method for preparing buprenorphine free base from an acetatesalt of buprenorphine, e.g., from buprenorphine acetate tetrahydrate,comprises:

(a) heating an admixture of an acetate salt of buprenorphine and anaqueous solution to provide precipitated buprenorphine free base; and

(b) filtering the admixture of step (a) to provide the buprenorphinefree base from the precipitate.

In some embodiments of this fourth method for preparing buprenorphinefree base from an acetate salt of buprenorphine, the aqueous solutionconsists essentially of water. In some embodiments of this fourth methodfor preparing buprenorphine free base from an acetate salt ofbuprenorphine, the aqueous solution comprises a mixture of water and analcohol. In some embodiments, in the mixture of water and alcohol thealcohol comprises IPA. In some embodiments, in the mixture of water andalcohol the alcohol is IPA. In some embodiments, the water and alcoholmixture is from about 95:5 to about 50:50 water:alcohol by volume, orfrom about 90:10 to about 60:40 water:alcohol by volume, or from about85:15 to about 70:30 water:alcohol by volume. In some embodiments, thewater and alcohol mixture is about 80:20 water:alcohol by volume. Insome embodiments, the water and alcohol mixture is from about 95:5 toabout 50:50 water:IPA by volume, or from about 90:10 to about 60:40water:IPA by volume, or from about 85:15 to about 70:30 water:IPA byvolume. In some embodiments, the water and alcohol mixture is about80:20 water:IPA by volume.

In some embodiments of this fourth method for preparing buprenorphinefree base, the admixture is heated to a temperature of from about 70° C.to about 90° C.

In some embodiments, the fourth method further comprises washing thesolid filtered product of step (b) with a second aqueous solution one ormore times. The second aqueous solution can be water or a mixture ofwater and alcohol as above.

In some embodiments, the fourth method further comprises the step ofdrying the solid filtered solid product of step (b).

In some embodiments of this fourth method, acetic acid in the final freebase preparation of buprenorphine is present at less than about 0.7 wt%, less than about 0.5 wt %, less than about 0.3 wt %, less than about0.2 wt %, or less than about 0.1 wt %.

In another aspect, the disclosure provides the buprenorphine free baseprepared by the fourth method, or by any variations thereof describedabove. In some embodiments, the buprenorphine free base prepared by thefourth method is essentially free of impurities.

In some embodiments, the buprenorphine free base prepared by the fourthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (10).

In some embodiments, the buprenorphine free base prepared by the fourthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (11).

In some embodiments, the buprenorphine free base prepared by the fourthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (12).

In some embodiments, the buprenorphine free base prepared by the fourthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (13).

In some embodiments, the buprenorphine free base prepared by the fourthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (14).

In some embodiments, the buprenorphine free base prepared by the fourthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (15).

In some embodiments, for the buprenorphine free base prepared by thefourth method, the combined level of impurities of the compounds offormulae (10), (11), (12), (13), (14), and (15), is about 0.70 wt % orless, about 0.65 wt % or less, about 0.60 wt % or less, about 0.55 wt %or less, about 0.50 wt % or less, about 0.45 wt % or less, about 0.40 wt% or less, about 0.35 wt % or less, about 0.30 wt % or less, about 0.25wt % or less, or about 0.20 wt % or less.

In some embodiments, for the buprenorphine free base prepared by thefourth method, the combined level of impurities of the compounds offormulae (10), (11), (12), (13), (14), and (15), and any other impurityor impurities not specifically identified herein, is about 0.75 wt % orless, about 0.70 wt % or less, about 0.65 wt % or less, about 0.60 wt %or less, about 0.55 wt % or less, about 0.50 wt % or less, about 0.45 wt% or less, about 0.40 wt % or less, about 0.35 wt % or less, about 0.30wt % or less, about 0.25 wt % or less, or about 0.20 wt % or less.

A fifth method for preparing buprenorphine free base from an acetatesalt of buprenorphine, e.g., from buprenorphine acetate tetrahydrate,comprises:

(a) mixing an acetate salt of buprenorphine in a solvent to form anadmixture;

(b) refluxing the admixture at a reflux temperature and removing theacetate as acetic acid in the vapor phase;

(c) cooling the admixture to provide precipitated buprenorphine freebase; and

(d) isolating the buprenorphine free base.

In some embodiments of this fifth method for preparing buprenorphinefree base from an acetate salt of buprenorphine, the isolating of step(d) comprises filtering the precipitated buprenorphine free base of step(c).

In some embodiments of this fifth method, the solvent comprises anorganic solvent. In some embodiments, the organic solvent can beselected from hexane, heptane, IPA, methanol, ethanol, n-propanol,n-butanol, iso-butanol, tert-butanol, acetonitrile, ethyl acetate,methyl ethyl ketone, methyl iso-butyl ketone, cyclohexane, toluene,tetrahydrofuran, and any mixture of two or more thereof.

In any of the above embodiments of the fifth method, the removing of theacetic acid can be done using a condenser in combination with adistillation head or a Dean-Stark trap.

In some embodiments of this fifth method, acetic acid in the final freebase preparation of buprenorphine is present at less than about 0.7 wt%, less than about 0.5 wt %, less than about 0.3 wt %, less than about0.2 wt %, or less than about 0.1 wt %.

In another aspect, the disclosure provides buprenorphine free baseprepared by the fifth method, or by any variations thereof describedabove. In some embodiments, the buprenorphine free base prepared by thefifth method is essentially free of impurities.

In some embodiments, the buprenorphine free base prepared by the fifthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (10).

In some embodiments, the buprenorphine free base prepared by the fifthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (11).

In some embodiments, the buprenorphine free base prepared by the fifthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (12).

In some embodiments, the buprenorphine free base prepared by the fifthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (13).

In some embodiments, the buprenorphine free base prepared by the fifthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (14).

In some embodiments, the buprenorphine free base prepared by the fifthmethod comprises about 0.10 wt % or less, about 0.09 wt % or less, about0.08 wt % or less, about 0.07 wt % or less, about 0.06 wt % or less, orabout 0.05 wt % or less of an impurity represented by the compound offormula (15).

In some embodiments, for the buprenorphine free base prepared by thefifth method, the combined level of impurities of the compounds offormulae (10), (11), (12), (13), (14), and (15), is about 0.70 wt % orless, about 0.65 wt % or less, about 0.60 wt % or less, about 0.55 wt %or less, about 0.50 wt % or less, about 0.45 wt % or less, about 0.40 wt% or less, about 0.35 wt % or less, about 0.30 wt % or less, about 0.25wt % or less, or about 0.20 wt % or less.

In some embodiments, for the buprenorphine free base prepared by thefifth method, the combined level of impurities of the compounds offormulae (10), (11), (12), (13), (14), and (15), and any other impurityor impurities not specifically identified herein, is about 0.75 wt % orless, about 0.70 wt % or less, about 0.65 wt % or less, about 0.60 wt %or less, about 0.55 wt % or less, about 0.50 wt % or less, about 0.45 wt% or less, about 0.40 wt % or less, about 0.35 wt % or less, about 0.30wt % or less, about 0.25 wt % or less, or about 0.20 wt % or less.

In a further aspect, the disclosure further provides other buprenorphinesalts prepared from the free base, where the free base is prepared froman acetate salt of buprenorphine, as described herein. Accordingly, insome embodiments, the buprenorphine salt can be represented by formula(1c),

or a solvate thereof;

where X^(n−) is an anion and n is 1, 2, or 3. In certain embodiments,X^(n−) is an anion selected from the group consisting of F⁻, Cl⁻, Br⁻,I⁻, valerate, acetate, meconate, salicylate, barbiturate, succinate,tartrate, maleate, fumarate, citrate, methanesulfonate, tosylate,trifluoroacetate, oxalate, perchlorate, NO₃ ⁻, HSO₄ ⁻, SO₄ ²⁻, H₂PO₄ ⁻,HPO₄ ²⁻, PO₄ ³⁻, [(NH₄)HPO₄]⁻, [(NH₄)₂PO₄]⁻, and HCOO⁻. In anotherembodiment, X^(n−) is Cl⁻.

A salt of formula (1c) can be obtained by adding an acid H⁺ _(n)X^(n−)to the buprenorphine free base.

In some embodiments, the acid H⁺ _(n)X^(n−) is selected from the groupconsisting of HCl, H₂SO₄, H₃PO₄, and HCOOH. In another embodiment, theacid H⁺ _(n)X^(n−) is HCl.

In some embodiments, the amount of acid added to the buprenorphine freebase is from about 0.5 molar equivalents to about 10 molar equivalentsbased on the total molar equivalents of the free base present in thecomposition. In some embodiments, the amount of acid is from about 1molar equivalent to about 6 molar equivalents. In some embodiments, theamount of acid is from about 2 molar equivalents to about 3 molarequivalents. In some embodiments, the amount of acid is from about 2.2molar equivalents to about 2.6 molar equivalents.

In some embodiments, the salt of formula (1c) can be an anhydrate, asolvate, or a hydrate. In some embodiments, the salt of formula (1c) isan anhydrate. In some embodiments, the salt of formula (1c) is a hydrateand the hydrate is a monohydrate, dihydrate, trihydrate, tetrahydrate,pentahydrate, or hexahydrate. In some embodiments, the hydrate is atetrahydrate.

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (10):

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (11):

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (12):

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (13):

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (14):

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (15):

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (16):

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (17):

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (18):

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods comprises about 0.10 wt % or less, about 0.09 wt% or less, about 0.08 wt % or less, about 0.07 wt % or less, about 0.06wt % or less, or about 0.05 wt % or less of an impurity represented bythe compound of formula (19):

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the methods above comprises about 0.10 wt % or less,about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % orless, about 0.06 wt % or less, or about 0.05 wt % or less of an impurityrepresented by the compound of formula (10):

or a salt thereof.

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the aforementioned methods comprises about 0.10 wt %or less, about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt% or less, about 0.06 wt % or less, or about 0.05 wt % or less of animpurity represented by the compound of formula (11):

or a salt thereof.

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the methods above comprises about 0.10 wt % or less,about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % orless, about 0.06 wt % or less, or about 0.05 wt % or less of an impurityrepresented by the compound of formula (12):

or a salt thereof.

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the methods above comprises about 0.10 wt % or less,about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % orless, about 0.06 wt % or less, or about 0.05 wt % or less of an impurityrepresented by the compound of formula (13):

or a salt thereof.

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the methods above comprises about 0.10 wt % or less,about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % orless, about 0.06 wt % or less, or about 0.05 wt % or less of an impurityrepresented by the compound of formula (14):

or a salt thereof.

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the methods above comprises about 0.10 wt % or less,about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % orless, about 0.06 wt % or less, or about 0.05 wt % or less of an impurityrepresented by the compound of formula (15):

or a salt thereof.

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the methods above comprises about 0.10 wt % or less,about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % orless, about 0.06 wt % or less, or about 0.05 wt % or less of an impurityrepresented by the compound of formula (16):

or a salt thereof.

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the methods above comprises about 0.10 wt % or less,about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % orless, about 0.06 wt % or less, or about 0.05 wt % or less of an impurityrepresented by the compound of formula (17):

or a salt thereof.

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the methods above comprises about 0.10 wt % or less,about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % orless, about 0.06 wt % or less, or about 0.05 wt % or less of an impurityrepresented by the compound of formula (18):

or a salt thereof.

In some embodiments, a salt prepared from the buprenorphine free baseprepared by any of the methods above comprises about 0.10 wt % or less,about 0.09 wt % or less, about 0.08 wt % or less, about 0.07 wt % orless, about 0.06 wt % or less, or about 0.05 wt % or less of an impurityrepresented by the compound of formula (19):

or a salt thereof.

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods, and the salts and pharmaceutical compositionsprepared therefrom, are essentially free of impurities. In someembodiments, for the buprenorphine free base prepared by any of theaforementioned methods, and the salts prepared therefrom, the combinedlevel of impurities of the compounds of formulae (10), (11), (12), (13),(14), (15), (16), (17), (18), and (19) that may be present, is about0.70 wt % or less, about 0.65 wt % or less, about 0.60 wt % or less,about 0.55 wt % or less, about 0.50 wt % or less, about 0.45 wt % orless, about 0.40 wt % or less, about 0.35 wt % or less, about 0.30 wt %or less, about 0.25 wt % or less, or about 0.20 wt % or less.

In some embodiments, for the buprenorphine free base prepared by any ofthe aforementioned methods, and the salts prepared therefrom, the totalamount of impurities, including the combined level of impurities of thecompounds of formulae (10), (11), (12), (13), (14), (15), (16), (17),(18), and (19), is about 0.70 wt % or less, about 0.65 wt % or less,about 0.60 wt % or less, about 0.55 wt % or less, about 0.50 wt % orless, about 0.45 wt % or less, about 0.40 wt % or less, about 0.35 wt %or less, about 0.30 wt % or less, about 0.25 wt % or less, about 0.20 wt% or less, about 0.15 wt % or less, or about 0.10 wt % or less.

In some embodiments, for the free base preparation of buprenorphineprepared by any of the aforementioned methods, and the salts preparedtherefrom, the total amount of impurities, including the combined levelof impurities of the compounds of formulae (10), (11), (12), (13), (14),(15), (16), (17), (18), and (19) that may be present, and any otherimpurity or impurities not specifically identified herein, is about 0.75wt % or less, about 0.70 wt % or less, about 0.65 wt % or less, about0.60 wt % or less, about 0.55 wt % or less, about 0.50 wt % or less,about 0.45 wt % or less, about 0.40 wt % or less, about 0.35 wt % orless, about 0.30 wt % or less, about 0.25 wt %, about 0.20 wt % or less,about 0.15 wt % or less, or about 0.10 wt % or less.

In some embodiments, for the buprenorphine free base prepared by any ofthe methods above, and the salts and pharmaceutical compositionsprepared therefrom, the amount of specific impurities of the compoundsof formulae (10) through (19), particularly the compounds of formulae(10) through (15), is at or below the threshold level (or thresholdlimit) specified by the United States Pharmacopeia (“USP”), FDA, EMA, orICH monographs/guidelines for buprenorphine. In some embodiments, thebuprenorphine free base prepared by any of the methods above, and thesalts and pharmaceutical compositions prepared therefrom, have an amountof all of the impurities set out in the following Table 2 at or belowthe level of the threshold limit or the threshold value (in wt %)provided in Table 2.

TABLE 2 Impurity Measured Threshold Value (ICH/EMA Designation) ImpurityLevel¹ Threshold Limit² (EMA)² Compound of formula (10) ND <0.10% NMT0.20% (Impurity B) Compound of formula (11) ND NMT 0.10% NMT 0.15%(Impurity G) Compound of formula (12) 0.05% NMT 0.10% NMT 0.25%(Impurity H) Compound of formula (13) ND NMT 0.20% NMT 0.20% (ImpurityA) Compound of formula (14) 0.07% NMT 0.10% NMT 0.20% (Impurity J)Compound of formula (15) ND <0.10% None Provided (Impurity E) Compoundof formula (16) ND NMT 0.10% NMT 0.20% (Impurity F) Compound of formula(17) NT None Provided None Provided (Impurity I) Compound of formula(18) ND <0.10% None Provided (Impurity D) Compound of formula (19) ND<0.10% None Provided (Impurity C) Impurities not specifically 0.00% NMT0.10% NMT 0.10% identified herein Total Impurity 0.12% NMT 0.65% NMT0.70% ¹ND = Not Detected, NT = Not Tested ²NMT = Not More Than

In some embodiments, the buprenorphine free base prepared by any of themethods above, and the salts and pharmaceutical compositions preparedtherefrom, are characterized by a measured impurity profile for all ofthe impurities set out in Table 2 above which is at or below the levelof the measured impurity profile provided in Table 2.

In some embodiments, the buprenorphine free base prepared by any of theaforementioned methods is converted into a pharmaceutically acceptablesalt thereof by reaction of the buprenorphine free base with anappropriate acid according to the guidance in the present disclosure orby any of a variety of known methods in view of the present disclosure.In one embodiment, the buprenorphine free base prepared by any of theaforementioned methods is converted into buprenorphine hydrochloride bythe reaction of buprenorphine free base with HCl. In one embodiment, thebuprenorphine free base prepared by any of the methods above isconverted into the levulinic acid-salt of buprenorphine by the reactionof buprenorphine free base with levulinic acid.

4.5 Pharmaceutical Compositions

In another aspect, the disclosure further provides pharmaceuticalcompositions of buprenorphine compounds prepared according to themethods described herein, including the corresponding salts, solvates,hydrates, and crystalline forms, and particularly pharmaceuticallyacceptable salts of buprenorphine.

Accordingly, in some embodiments, a pharmaceutical composition of thedisclosure comprises an acetate salt of buprenorphine. In someembodiments, a pharmaceutical composition of the disclosure comprises ahydrochloride salt of buprenorphine. In some embodiments, apharmaceutical composition of the disclosure comprises a levulinate saltof buprenorphine. In some embodiments, the pharmaceutical compositioncomprises buprenorphine in anhydrous form. In some embodiments, thepharmaceutical composition comprises a hydrate of buprenorphine. In someembodiments, the pharmaceutical composition comprises a hydrate ofbuprenorphine acetate. In some embodiments, the pharmaceuticalcomposition comprises buprenorphine acetate tetrahydrate.

In some embodiments, the pharmaceutical composition comprisesbuprenorphine, a hydrate thereof, or a particular crystalline formthereof, prepared by any of the aforementioned methods for preparing thecompound of formula (1), its hydrates, and crystalline form as describedherein, particularly in Section 4.3 of the disclosure and in theexamples.

In some embodiments, the pharmaceutical composition comprisesbuprenorphine, a hydrate thereof, or a particular crystalline formthereof having the level of impurities described herein, including thelevel of impurities for the compounds of formulae (10), (11), (12),(13), (14), and (15), as described herein.

In some embodiments, the pharmaceutical composition comprisesbuprenorphine free base prepared by a method of the disclosure.

In some embodiments, the pharmaceutical composition comprisesbuprenorphine free base having the level of impurities described herein,including the level of impurities for one or more of the compounds offormulae (10), (11), (12), (13), (14), and (15), as described herein.

As further described herein, the buprenorphine compounds andcompositions of the disclosure can be used alone or in combination withother therapeutic agents to treat a Condition in an animal in needthereof. Accordingly, in some embodiments the pharmaceutical compositionis formulated to contain a buprenorphine compound of the disclosurewithout other therapeutic agents. In other embodiments, thepharmaceutical composition is formulated to contain a buprenorphinecompound of the disclosure (a first therapeutic agent) and one or moreother therapeutic agents (e.g., one or more second therapeuticagent(s)).

Pharmaceutical compositions of the disclosure can take the form ofsolutions, suspensions, emulsions, tablets, pills, pellets,multi-particulates, capsules, capsules containing liquids, capsulescontaining powders, capsules containing beads or multi-particulates,lozenges, immediate-release oral formulations, controlled-releaseformulations, sustained-release formulations, suppositories, aerosols,sprays, formulations for inhalation, transdermal delivery systems (e.g.,patches, aerosols, sprays, gels, salves, ointments), intra-ocularformulations, transmucosal delivery devices (e.g., for gingival, buccalintra-nasal, rectal, vaginal, or sub-lingual delivery), or any otherform suitable for use. In some embodiments, the composition is in theform of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examplesof suitable pharmaceutical excipients are described in Radebough et al.,“Preformulation,” pp. 1447-1676 in Remington's Pharmaceutical SciencesVol. 2 (Gennaro, ed., 19^(th) Ed., Mack Publishing, Easton, Pa., 1995),incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the disclosurepreferably comprise a suitable amount of one or more pharmaceuticallyacceptable excipients to provide the form for proper administration toan animal by the particular route. Such pharmaceutical excipients can beselected from diluents, suspending agents, solubilizers, binders,disintegrants, buffers, glidants, preservatives, coloring agents,anti-oxidants, lubricants, and the like. Pharmaceutical excipients canbe a liquid, such as water or an oil, including those of petroleum,animal, vegetable, or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil, and the like. Pharmaceutical excipients can besaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating, and coloring agents can be used. In a preferredembodiment, a pharmaceutically acceptable excipient is sterile whenadministered to an animal. Water is a particularly useful excipient whenthe pharmaceutical composition is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid excipients, particularly for injectable solutions.Suitable pharmaceutical excipients also include starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. Thecompositions, if desired, can also contain minor amounts of wettingagents, emulsifying agents, or pH buffering agents. Specific examples ofpharmaceutically acceptable carriers and excipients that can be used toformulate particular dosage forms are described in the Handbook ofPharmaceutical Excipients, (Amer. Pharmaceutical Ass'n, Washington,D.C., 1986).

In some embodiments, the buprenorphine compounds or the pharmaceuticalcompositions of the disclosure are formulated for transdermaladministration, such as by using a transdermal patch. A transdermalpatch can comprise, e.g., a buprenorphine compound of the disclosurecontained in a reservoir or a matrix, and an adhesive, which allows thetransdermal device to adhere to the skin and also allows the passage ofthe buprenorphine compound of the disclosure from the transdermal devicethrough the skin of an animal. In another embodiment, a transdermalpatch can comprise, e.g., a pharmaceutical composition comprising abuprenorphine compound of the disclosure contained in a reservoir or amatrix, and an adhesive, which allows the transdermal device to adhereto the skin and also allows the passage of the pharmaceuticalcomposition from the transdermal device through the skin of the animal.

Suitable transdermal formulations are described in U.S. Pat. Nos.6,264,980, 6,344,211, RE41,408, RE41,489, and RE41,571; U.S. Pat.Application Publication Nos. 2010/0119585 and 2014/0363487; andInternational Patent Publication Nos. WO 2013/088254, WO 2014/090921,and WO 2014/195352, each of which is incorporated herein by reference. Asuitable transdermal formulation comprises a buprenorphine (e.g.,buprenorphine free base) impermeable backing layer and apressure-sensitive adhesive layer on the buprenorphine-impermeablebacking layer. The pressure-sensitive adhesive layer is the skin contactlayer. The pressure-sensitive adhesive layer comprises at least onepolymer-based pressure-sensitive adhesive, an analgesically effectiveamount of buprenorphine free base or a pharmaceutically acceptable saltthereof, and a carboxylic acid. The carboxylic acid is present in anamount sufficient so that the analgesically effective amount ofbuprenorphine is solubilized in the carboxylic acid to form a mixtureand so that the carboxylic acid-buprenorphine mixture forms disperseddeposits in the pressure-sensitive adhesive layer. The carboxylic acidis selected from oleic acid, linoleic acid, linolenic acid, levulinicacid, and mixtures thereof. In one embodiment, the carboxylic acid islevulinic acid. In another embodiment, the pressure-sensitive adhesiveis based on polysiloxane. In another embodiment, the pressure-sensitiveadhesive is based on polysiloxane and the carboxylic acid is levulinicacid.

In some embodiments, the buprenorphine is administered in thetransdermal system to provide, e.g., a dosing interval of about 24hours, a dosing interval of about 3 days, or a dosing interval of about7 days. In some embodiments, the transdermal buprenorphine system can beformulated to administer buprenorphine, e.g., at a rate of from about0.001 mcg/hour to about 50 mcg/hour, or from about 0.01 mcg/hour toabout 40 mcg/hour, or from about 0.05 mcg/hour to about 30 mcg/hour, orfrom about 0.1 mcg/hour to about 20 mcg/hour or from about 0.5 mcg/hourto about 10 mcg/hour. In some embodiments, the transdermal buprenorphinesystem can be formulated to administer buprenorphine, e.g., at a rate offrom about 0.001 mcg/hour to about 5 mcg/hour, or from about 0.01mcg/hour to about 4 mcg/hour, or from about 0.05 mcg/hour to about 3mcg/hour, or from about 0.1 mcg/hour to about 2 mcg/hour, or from about0.5 mcg/hour to about 1 mcg/hour. In some embodiments, the transdermalbuprenorphine system can be formulated to administer buprenorphine,e.g., at a rate of about 50 mcg/hour, about 40 mcg/hour, about 30mcg/hour, about 20 mcg/hour, about 10 mcg/hour, about 5 mcg/hour, about4 mcg/hour, about 3 mcg/hour, about 2 mcg/hour, about 1 mcg/hour, about0.5 mcg/hour, about 0.1 mcg/hour, about 0.05 mcg/hour, about 0.01mcg/hour, or about 0.001 mcg/hour.

In some embodiments, the pharmaceutical compositions are formulated fororal administration. A pharmaceutical composition of the disclosure tobe orally delivered can be in the form of tablets, capsules, gelcaps,caplets, lozenges, aqueous or oily solutions, suspensions, granules,powders, emulsions, syrups, quick dissolving tablets (such as forsub-lingual delivery), quick dissolving strips (such as for buccaldelivery), or elixirs, for example. When the buprenorphine or other(e.g., a second) therapeutic agent is incorporated into oral tablets,such tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, multiply compressed or multiply layered.

An orally administered pharmaceutical composition can contain one ormore additional agents such as, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,and stabilizers, to provide stable, pharmaceutically palatable dosageforms. Techniques and compositions for making solid oral dosage formsare described in Pharmaceutical Dosage Forms: Tablets (Lieberman et al.,eds., 2^(nd) Ed., Marcel Dekker, Inc., 1989 and 1990). Techniques andcompositions for making tablets (compressed and molded), capsules (hardand soft gelatin) and pills are also described in King, “Tablets,Capsules, and Pills,” pp. 1553-1593 in Remington's PharmaceuticalSciences (Osol, ed., 16^(th) Ed Mack Publishing, Easton, Pa., 1980).Liquid oral dosage forms can include both aqueous and nonaqueoussolutions, emulsions, and suspensions. Techniques and compositions formaking liquid oral dosage forms are described in Pharmaceutical DosageForms: Disperse Systems (Lieberman et al., eds., 2^(nd) Ed., MarcelDekker, Inc., 1996 and 1998).

When the buprenorphine or the second therapeutic agent is formulated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation can be in the form of a suspension,solution, or emulsion in an oily or aqueous vehicle, and suchformulations can further comprise pharmaceutically necessary additivessuch as one or more buffering agents, stabilizing agents, suspendingagents, dispersing agents, and the like. When the formulation of thedisclosure is to be injected parenterally, it can be, e.g., in the formof an isotonic sterile solution. The formulation can also be in the formof a powder (e.g., lyophilized) adapted for reconstitution as aninjectable formulation.

In some embodiments, a pharmaceutical composition of the disclosure isadapted for intravenous administration. Typically, such compositionscomprise sterile isotonic aqueous buffer. Where necessary, thecompositions can also include a solubilizing agent. A pharmaceuticalcomposition for intravenous administration can optionally include alocal anesthetic such as benzocaine or prilocaine to lessen pain at thesite of the injection. Generally, the ingredients are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water-free concentrate in a hermetically sealedcontainer such as an ampule or sachette indicating the quantity ofactive agent. Where the pharmaceutical composition of the disclosure isto be administered by infusion, it can be dispensed, for example, withan infusion bottle containing sterile pharmaceutical grade water orsaline. When the pharmaceutical composition of the disclosure isadministered by injection, an ampule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

When a pharmaceutical compositions of the disclosure is to beadministered by inhalation, it can be formulated into a dry aerosol, oran aqueous or partially aqueous solution.

In some embodiments, the pharmaceutical compositions of the disclosurecan be delivered in vesicles, in particular a liposome (see Langer, “NewMethods of Drug Delivery,” Science 249:1527-1533 (1990) (hereafter“Langer”) and Treat et al., “Liposome Encapsulated DoxorubicinPreliminary Results of Phase I and Phase II Trials,” pp. 317-327 and353-365 in Liposomes in the Therapy of Infectious Disease and Cancer(1989)).

In some embodiments, the pharmaceutical compositions of the disclosurecan be delivered in an immediate release form. In other embodiments, thepharmaceutical compositions of the disclosure can be delivered in acontrolled-release system or sustained-release system.Controlled-release or sustained-release pharmaceutical compositions canhave a common goal of improving drug therapy compared to the resultsachieved by their non-controlled or non-sustained-release counterparts.Advantages of controlled-release or sustained-release compositionsinclude extended activity of the drug, reduced dosage frequency, andincreased compliance. In addition, controlled-release orsustained-release compositions can favorably affect the time of onset ofaction or other characteristics, such as blood levels of thebuprenorphine and/or another therapeutic agent, and can thus reduce theoccurrence of adverse side effects.

Controlled-release or sustained-release compositions can have animmediate release component that initially releases an amount of thebuprenorphine or another therapeutic agent to promptly produce thedesired therapeutic or prophylactic effect, and then gradually andcontinually releases other amounts of the buprenorphine or anothertherapeutic agent to maintain a level of therapeutic or prophylacticeffect over an extended period of time. To maintain a constant level ofthe buprenorphine and/or another therapeutic agent in the body, thepharmaceutical composition can be adapted to release the activeingredient(s) from the dosage form at a rate that will replace theamount of active(s) being metabolized and excreted from the body.Controlled or sustained release of an active ingredient can be triggeredby any of various conditions, including but not limited to, changes inpH, changes in temperature, concentration or availability of enzymes,concentration or availability of water, or other physiologicalconditions or compounds.

Controlled-release and sustained-release means which may be adapted foruse according to the disclosure may be selected from those known in theart. Examples include, but are not limited to, those described in U.S.Pat. Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719,5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476,5,354,556, and 5,733,566, each of which is incorporated herein byreference. Such dosage forms can be used to provide controlled-releaseor sustained-release of one or both of the active ingredients using, forexample, hydropropylmethyl cellulose, other polymer matrices, gels,permeable membranes, osmotic systems, multilayer coatings,microparticles, multiparticulates, liposomes, microspheres, or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled-release or sustained-releaseformulations known in the art, including those described herein, can bereadily adapted for use with the active ingredients of the disclosure.See also Goodson, “Dental Applications,” in Medical Applications ofControlled Release, Vol. 2, Applications and Evaluation, Langer andWise, eds., CRC Press, Chapter 6, pp. 115-138 (1984). Othercontrolled-release or sustained-release systems that are discussed inthe review by Langer can be adapted for use according to the disclosure.In some embodiments, a pump can be used, e.g., Saudek et al., “APreliminary Trial of the Programmable Implantable Medication System forInsulin Delivery,” New Engl. J. Med. 321:574-579 (1989)). In someembodiments, polymeric materials can be implanted, e.g., Langer et al.,“Chemical and Physical Structure of Polymers as Carriers for ControlledRelease of Bioactive Agents: A Review,” J. Macromol. Sci. Rev. Macromol.Chem. C23(1):61-126 (1983).

When in oral dosage form as a tablet or pill, a pharmaceuticalcomposition of the disclosure can be coated to delay disintegration andabsorption in the gastrointestinal tract thereby providing targetedrelease to a particular portion of the gastrointestinal tract, orproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound (osmagent) can also be suitable for orally administeredcompositions. In these latter platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent through an aperture in the wall of the dosageform. Such delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions preferably includestandard excipients of pharmaceutical grade selected, for example, frommannitol, lactose, starch, magnesium stearate, sodium saccharin,cellulose, and magnesium carbonate, among others.

In some embodiments, the dosage form can further comprise at least onepolymer. Examples of polymers include but are not limited to amaltodextrin polymer comprising the formula (C₆H₁₂O₅)_(n) where n isfrom 3 to 7,500, a poly(alkylene oxide) such as a poly(ethylene oxide)and a poly(propylene oxide), an alkali carboxyalkylcellulose, where thealkali is sodium or potassium and the alkyl is methyl, ethyl, propyl, orbutyl, and a copolymer of ethylene-acrylic acid, ethylene-methacrylicacid, or ethylene-ethacrylic acid.

In some embodiments, the polymer is selected from the group consistingof a polyalkylene oxide and a carboxyalkylcellulose. The polyalkyleneoxide may be a member selected from the group consisting ofpolymethylene oxide, polyethylene oxide (“PEO”), and polypropyleneoxide. The carboxyalkylcellulose may be a member selected from the groupconsisting of alkali carboxyalkylcellulose, sodiumcarboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethylcellulose, carboxyethylhydroxyethylcelluloseand carboxymethylhydroxypropylcellulose.

In some embodiments, the PEO polymer in the dosage form is a highmolecular weight PEO, i.e., having a molecular weight of at least 0.5million in one embodiment and, in another embodiment, at least 1 millionup to 15 million. The PEO molecular weight is determined by rheologicalmeasurements, e.g., as disclosed in U.S. Pat. No. 8,075,872 at column 6,lines 5-14, incorporated herein by reference. High molecular weight PEOpolymers have a viscosity at 25° C. of 4500 cP to 17600 cP measured on a5 wt % aqueous solution using a model RVF Brookfield viscosimeter(spindle no. 2/rotational speed 2 rpm), of 400 cP to 4000 cP measured ona 2 wt % aqueous solution using the stated viscosimeter (spindle no. 1or 3/rotational speed 10 rpm), or of 1650 cP to 10000 cP measured on a 1wt % aqueous solution using the stated viscosimeter (spindle no.2/rotational speed 2 rpm).

Dosage forms containing polyalkylene oxide, particularly PEO, and moreparticularly high molecular weight PEO, each having a breaking strengthof at least 500 N, are advantageous because, due to the hardness theyimpart to, e.g., a tablet, such dosage form cannot be pulverized inconventional comminution means available to a drug abuser, such as amortar and pestle. This virtually rules out oral or parenteral, inparticular intravenous or nasal, abuse. Tamper-resistant unpulverizabledosage forms are disclosed in, e.g., U.S. Pat. Nos. 8,075,872,8,114,383, 8,192,722, and 8,309,060, incorporated herein by reference.

In some embodiments, the carboxyalkylcellulose polymer in the dosageform is selected so as to impart a gel-like quality to a dosage formthat is tampered with, thereby reducing the potential for abuse of thebuprenorphine compounds of the disclosure in the dosage form throughspoiling or hindering the pleasure of obtaining a rapid high from thetampered dosage form due to the gel-like consistency. For example, thegel-like consistency, when in contact with the mucous membrane, preventsthe abuse of the tampered dosage form by minimizing absorption (e.g., inthe nasal passages) or provides substantial difficulty in injecting thetampered dosage form (e.g., due to difficulty pushing the tampereddosage form through a syringe or pain upon administration) because ofthe high viscosity imparted to the tampered dosage form.

A carboxyalkylcellulose gelling agent may be added to the formulation ina ratio of gelling agent:buprenorphine compounds of the disclosure offrom about 1:40 to about 40:1 by weight in one embodiment, or from about1:1 to about 30:1 by weight in another embodiment, or from about 2:1 toabout 10:1 by weight in another embodiment so that the dosage form formsa viscous gel after the dosage form is tampered with, dissolved in anaqueous liquid (in from about 0.5 mL to about 10 mL and preferably fromabout 1 mL to about 5 mL of the aqueous liquid), causing the resultingmixture to have a viscosity of at least about 10 cP in one embodimentand, in another embodiment, a viscosity of at least about 60 cP. Inanother embodiment, the carboxyalkylcellulose gelling agent causes thedosage form to form a viscous gel after the dosage form is tamperedwith, dissolved in an aqueous liquid (in from about 0.5 mL to about 10mL and preferably from about 1 mL to about 5 mL of the aqueous liquid)and then heated (e.g., to greater than about 45° C.), causing theresulting mixture to have a viscosity of at least about 10 cP in oneembodiment and, in another embodiment, a viscosity of at least about 60cP. Tamper-resistant dosage forms containing a gelling agent aredisclosed in, e.g., U.S. Pat. Nos. 7,842,307, 8,337,888, 8,524,275,8,529,948, and 8,609,683, incorporated herein by reference.

4.6 Methods of Use

The buprenorphine compounds of the disclosure are useful in human andveterinary medicine. As further described herein, the buprenorphinecompounds are useful for treating or preventing a Condition in an animalin need thereof. When administered to an animal, the buprenorphinecompounds can be administered as a component of a composition thatcomprises one or more pharmaceutically acceptable carriers orexcipients. The compositions can be administered by any convenient routeand also administered together with a second therapeutically activeagent. Administration can be systemic or local.

In some embodiments, the methods of administration include, but are notlimited to, intradermal, intramuscular, intraperitoneal, parenteral,intravenous, subcutaneous, intranasal, epidural, oral, sublingual,intracerebral, intravaginal, transdermal (e.g., via a patch), rectal, byinhalation, transmucosal, or topical, particularly to the ears, nose,eyes, or skin. The method of administration is left to the discretion ofthe practitioner. In some instances, administration will result in therelease of the buprenorphine compound into the bloodstream. In otherinstances, administration will result in only local release of thebuprenorphine compound.

In some embodiments, the buprenorphine compounds and pharmaceuticalcompositions of the disclosure can be used to treat Conditions known tobe treated using buprenorphine, either alone or in combination withother therapeutic agents. In some embodiments, the buprenorphinecompounds and pharmaceutical compositions of the disclosure can be usedto treat a Condition selected from pain and drug addiction. In addition,the buprenorphine compounds of the disclosure can be used in combinationwith other opioids to help mitigate adverse opioid side effects such asrespiratory depression, gastrointestinal motility disorders (e.g.,constipation), euphoria, and the like.

Accordingly, in some embodiments, the buprenorphine compounds of thedisclosure and the pharmaceutically acceptable compositions thereof, canbe used to treat or prevent acute pain or chronic pain in animals.Examples of pain that can be treated or prevented using buprenorphineinclude, but are not limited to, cancer pain, neuropathic pain, laborpain, myocardial infarction pain, pancreatic pain, colic pain,post-operative pain, headache pain, muscle pain, arthritic pain, andpain associated with a periodontal disease, including gingivitis andperiodontitis.

In some embodiments, the buprenorphine compounds of the disclosure, andthe pharmaceutically acceptable compositions thereof, can also be usedfor treating or preventing pain associated with inflammation or with aninflammatory disease in an animal. Such pain can arise where there is aninflammation of the body tissue which can be a local inflammatoryresponse and/or a systemic inflammation. For example, the buprenorphinecompounds can be used to treat or prevent pain associated withinflammatory diseases including, but not limited to: organ transplantrejection; reoxygenation injury resulting from organ transplantation(see Grupp et al., “Protection against Hypoxia-reoxygenation in theAbsence of Poly (ADP-ribose) Synthetase in Isolated Working Hearts,” J.Mol. Cell Cardiol. 31:297-303 (1999)) including, but not limited to,transplantation of the heart, lung, liver, or kidney; chronicinflammatory diseases of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel diseases, such as ileitis,ulcerative colitis, Barrett's syndrome, and Crohn's disease;inflammatory lung diseases, such as asthma, adult respiratory distresssyndrome, and chronic obstructive airway disease; inflammatory diseasesof the eye, including corneal dystrophy, trachoma, onchocerciasis,uveitis, sympathetic ophthalmitis and endophthalmitis; chronicinflammatory diseases of the gum, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney, including uremic complications, glomerulonephritis andnephrosis; inflammatory diseases of the skin, includingsclerodermatitis, psoriasis and eczema; inflammatory diseases of thecentral nervous system, including chronic demyelinating diseases of thenervous system, multiple sclerosis, AIDS-related neurodegeneration andAlzheimer s disease, infectious meningitis, encephalomyelitis,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosisand viral or autoimmune encephalitis; autoimmune diseases, includingType I and Type II diabetes mellitus; diabetic complications, including,but not limited to, diabetic cataract, glaucoma, retinopathy,nephropathy (such as microalbuminuria and progressive diabeticnephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy,gangrene of the feet, atherosclerotic coronary arterial disease,peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma,foot ulcers, joint problems, and a skin or mucous membrane complication(such as an infection, a shin spot, a candidal infection or necrobiosislipoidica diabeticorum); immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory diseases of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andatherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. Thebuprenorphine compounds of the disclosure can also be used forinhibiting, treating, or preventing pain associated with inflammatorydisease that can, for example, be a systemic inflammation of the body,exemplified by gram-positive or gram negative shock, hemorrhagic oranaphylactic shock, or shock induced by cancer chemotherapy in responseto pro-inflammatory cytokines, e.g., shock associated withpro-inflammatory cytokines. Such shock can be induced, e.g., by achemotherapeutic agent that is administered as a treatment for cancer.

The buprenorphine compounds of the disclosure, or a pharmaceuticallyacceptable composition thereof, can also be used to treat or preventpain associated with nerve injury (i.e., neuropathic pain). Chronicneuropathic pain is a heterogeneous disease state with an unclearetiology. In chronic neuropathic pain, the pain can be mediated bymultiple mechanisms. This type of pain generally arises from injury tothe peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain differs fromacute pain in that, for chronic neuropathic pain sufferers, the abnormalpain sensations can be described as spontaneous pain, continuoussuperficial burning and/or deep aching pain. The pain can be evoked byheat-, cold-, and mechano-hyperalgesia, or by heat-, cold-, ormechano-allodynia.

Chronic neuropathic pain can be caused by injury or infection ofperipheral sensory nerves. It includes, but is not limited to, pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain can also be caused by nerve damage from chronicalcoholism, human immunodeficiency virus infection, hypothyroidism,uremia, or vitamin deficiencies. Stroke (spinal or brain) and spinalcord injury can also induce neuropathic pain. Cancer-related neuropathicpain can result from tumor growth compression of adjacent nerves, brain,or spinal cord. In addition, cancer treatments, including chemotherapyand radiation therapy, can cause nerve injury. Neuropathic pain includesbut is not limited to pain caused by nerve injury such as, for example,the pain from which diabetics suffer.

In some embodiments, the buprenorphine compounds of the disclosure andthe pharmaceutical compositions thereof, can be used to treat or preventpain associated with osteoarthritis. Osteoarthritis (OA), also known asosteoarthrosis, degenerative arthritis, or degenerative joint disease,is a group of mechanical abnormalities involving degradation of joints,including articular cartilage and subchondral bone. Examples of OAtreatable or preventable using the buprenorphine compounds of thedisclosure include, but are not limited to, joint pain, joint stiffness,joint tenderness, joint locking, and joint effusion.

In some embodiments, the buprenorphine compounds of the disclosure andthe pharmaceutical compositions thereof, can be used to treat or preventthe Condition of drug addiction or drug abuse, particularly drugaddiction to or drug abuse of another opioid. In some embodiments, thebuprenorphine is administered concurrently with another opioid, wherethe buprenorphine, when administered in a relatively low dose, can serveto prevent, minimize, inhibit, ameliorate, or reverse the euphoriacaused by the other opioid.

In some embodiments, the buprenorphine compounds of the disclosure andthe pharmaceutical compositions thereof, can be used to treat or preventthe Condition of drug addiction or drug abuse of opioid agonistsselected from codeine, fentanyl, heroin, hydrocodone, hydromorphone,methadone, morphine, opium, oxycodone, oxymorphone, tramadol, andmixtures of any of the foregoing.

In some embodiments, the buprenorphine compounds of the disclosure andthe pharmaceutical compositions thereof, can be used in a relatively lowdose to treat, ameliorate, minimize, or prevent the Condition ofrespiratory depression, particularly caused by other opioids, such asmorphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, andfentanyl, among others, as disclosed in U.S. Pat. No. 8,946,253, whichis incorporated herein by reference.

In some embodiments, a buprenorphine compound of the disclosure or apharmaceutical composition thereof, can be used in a relatively low doseto treat, ameliorate, minimize, or prevent the Condition of a gutmotility disorder, such as decreased gastric motility, delayed gastricemptying, constipation, bloating and cramping. In particular, abuprenorphine compound of the disclosure or a pharmaceutical compositionthereof, can be used to treat the Condition of gut motility disorders(e.g., opioid induced constipation) caused by other opioids, such asmorphine, oxycodone, hydrocodone, and fentanyl.

The amount of the buprenorphine compound, or pharmaceutically acceptablecomposition thereof, that is effective in the treatment or prevention ofany of the Conditions described herein can be determined by standardclinical techniques. The precise dose to be employed will depend on theroute of administration and the seriousness of the Condition, and can bedetermined according to the judgment of a medical practitioner accordingto each animal's circumstances. Suitable effective dosage amounts,however, can, in some embodiments, range from about 0.01 mg/kg of bodyweight to about 2500 mg/kg of body weight. In some embodiments, theeffective dosage amount ranges from about 0.01 mg/kg of body weight toabout 100 mg/kg of body weight of the buprenorphine compounds; inanother embodiment, about 0.02 mg/kg to about 50 mg/kg of body weight;and in another embodiment, about 0.025 mg/kg to about 20 mg/kg of bodyweight.

In some embodiments, an effective dosage amount is administered aboutevery 24 h, about every 12 h, about every 8 h, about every 6 h, or aboutevery 4 h until the Condition is abated.

In some embodiments, an oral dosage form can be formulated to administera buprenorphine compound of the disclosure, e.g., at a dose of less thanabout 500 mg, less than about 400 mg, less than about 350 mg, less thanabout 300 mg, less than about 250 mg, less than about 200 mg, less thanabout 150 mg, less than about 100 mg, less than about 90 mg, less thanabout 80 mg, less than about 70 mg, less than about 60 mg, less thanabout 50 mg, less than about 40 mg, less than about 30 mg, less thanabout 20 mg, less than about 10 mg, less than about 9 mg, less thanabout 8 mg, less than about 7 mg, less than about 6 mg, less than about5 mg, less than about 4 mg, less than about 3 mg, less than about 2 mg,less than about 1 mg, less than about 0.9 mg, less than about 0.8 mg,less than about 0.7 mg, less than about 0.6 mg, less than about 0.5 mg,less than about 0.4 mg, less than about 0.3 mg, less than about 0.2 mgor less than about 0.1 mg.

In some embodiments, the oral dosage form can be formulated toadminister buprenorphine, e.g., at a dose of from about 1 mg to about500 mg, or from about 1 mg to about 400 mg, or from about 1 mg to about350 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about250 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about150 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about90 mg, or from about 1 mg to about 80 mg, or from about 1 mg to about 70mg, or from about 1 mg to about 60 mg, or from about 1 mg to about 50mg, or from about 1 mg to about 40 mg, or from about 1 mg to about 30mg.

In some embodiments, the oral dosage form can be formulated toadminister a buprenorphine compound of the disclosure, e.g., at a doseof from about 30 mg to about 500 mg, or from about 30 mg to about 400mg, or from about 30 mg to about 350 mg, or from about 30 mg to about300 mg, or from about 30 mg to about 250 mg, or from about 30 mg toabout 200 mg, or from about 30 mg to about 150 mg, or from about 30 mgto about 100 mg, or from about 30 mg to about 90 mg, or from about 30 mgto about 80 mg, or from about 30 mg to about 70 mg, or from about 30 mgto about 60 mg, or from about 30 mg to about 50 mg, or from about 30 mgto about 40 mg.

In some embodiments, the oral dosage form can be formulated toadminister a buprenorphine compound of the disclosure, e.g., at a doseof from about 0.1 mg to about 30 mg, or from about 0.2 mg to about 30mg, or from about 0.3 mg to about 30 mg, or from about 0.4 mg to about30 mg, or from about 0.5 mg to about 30 mg, or from about 0.6 mg toabout 30 mg, or from about 0.7 mg to about 30 mg, or from about 0.8 mgto about 30 mg, or from about 0.9 mg to about 30 mg, or from about 2 mgto about 30 mg, or from about 3 mg to about 30 mg, or from about 4 mg toabout 30 mg, or from about 5 mg to about 30 mg, or from about 6 mg toabout 30 mg, or from about 7 mg to about 30 mg, or from about 8 mg toabout 30 mg, or from about 9 mg to about 30 mg or from about 10 mg toabout 30 mg.

In some embodiments, the oral dosage form can be formulated toadminister a buprenorphine compound of the disclosure, e.g., at a doseof from about 3 mg to about 500 mg, or from about 3 mg to about 400 mg,or from about 3 mg to about 350 mg, or from about 3 mg to about 300 mg,or from about 3 mg to about 250 mg, or from about 3 mg to about 200 mg,or from about 3 mg to about 150 mg, or from about 3 mg to about 100 mg,or from about 3 mg to about 90 mg, or from about 3 mg to about 80 mg, orfrom about 3 mg to about 70 mg, or from about 3 mg to about 60 mg, orfrom about 3 mg to about 50 mg, or from about 3 mg to about 40 mg, orfrom about 3 mg to about 30 mg, or from about 3 mg to about 20 mg orfrom about 3 mg to about 10 mg.

In some embodiments, the oral dosage form can be formulated toadminister a buprenorphine compound of the disclosure, e.g., at a doseof from about 0.1 mg to about 3 mg, or from about 0.2 mg to about 3 mg,or from about 0.3 mg to about 3 mg, or from about 0.4 mg to about 3 mg,or from about 0.5 mg to about 3 mg, or from about 0.6 mg to about 3 mg,or from about 0.7 mg to about 3 mg, or from about 0.8 mg to about 3 mg,or from about 0.9 mg to about 3 mg, or from about 1 mg to about 3 mg, orfrom about 2 mg to about 3 mg.

In some embodiments, the buprenorphine compounds of the disclosure areadministered sublingually. A buprenorphine compound can be formulated ina sublingual formulation to provide, e.g., a dosing interval of about 4hours, a dosing interval of about 6 hours, a dosing interval of about 8hours, a dosing interval of about 12 hours, or a dosing interval ofabout 24 hours.

In some embodiments, the sublingual formulation can be formulated toadminister a buprenorphine compound of the disclosure, e.g., at a doseof from about 0.001 mg to about 10 mg, or from about 0.01 mg to about 8mg, or from about 0.05 mg to about 6 mg, or from about 0.1 mg to about 5mg or from about 0.5 mg to about 4 mg, or from about 1 mg to about 2 mg.

In some embodiments, the buprenorphine compounds of the disclosure areadministered in a transdermal system to provide, e.g., a dosing intervalof about 24 hours, a dosing interval of about 3 days, or a dosinginterval of about 7 days.

In some embodiments, the transdermal system can be formulated toadminister buprenorphine, e.g., at a rate from about 0.001 mcg/hour toabout 50 mcg/hour, or from about 0.01 mcg/hour to about 40 mcg/hour, orfrom about 0.05 mcg/hour to about 30 mcg/hour, or from about 0.1mcg/hour to about 20 mcg/hour or from about 0.5 mcg/hour to about 10mcg/hour.

In some embodiments, the transdermal system can be formulated toadminister buprenorphine, e.g., at a rate from about 0.001 mcg/hour toabout 5 mcg/hour, or from about 0.01 mcg/hour to about 4 mcg/hour, orfrom about 0.05 mcg/hour to about 3 mcg/hour, or from about 0.1 mcg/hourto about 2 mcg/hour, or from about 0.5 mcg/hour to about 1 mcg/hour.

In some embodiments, the transdermal system can be formulated toadminister buprenorphine, e.g., at a rate of about 50 mcg/hour, about 40mcg/hour, about 30 mcg/hour, about 20 mcg/hour, about 10 mcg/hour, about5 mcg/hour, about 4 mcg/hour, about 3 mcg/hour, about 2 mcg/hour, about1 mcg/hour, about 0.5 mcg/hour, about 0.1 mcg/hour, about 0.05 mcg/hour,about 0.01 mcg/hour, or about 0.001 mcg/hour.

In some embodiments, the buprenorphine compounds of the disclosure canbe administered by any route (e.g., oral, transdermal, transmucosal, orsubcutaneous) to provide at steady state, e.g., from about 0.001 mg/kgto about 1 mg/kg, or from about 0.005 mg/kg to about 0.5 mg/kg or fromabout 0.05 mg/kg to about 0.1 mg/kg. In other embodiments, thebuprenorphine compounds can be administered by any route (e.g., oral,transdermal, transmucosal, or subcutaneous) to provide at steady state,e.g., about 1 mg/kg, about 0.5 mg/kg, about 0.1 mg/kg, about 0.05 mg/kg,about 0.005 mg/kg or about 0.001 mg/kg. Where buprenorphine is used incombination with another therapeutic agent, the buprenorphine compoundsof the disclosure can be administered for any suitable time, e.g., forthe full duration of therapy with the other agent, or for a fraction ofthe full duration of therapy with the other agent.

In some embodiments, the buprenorphine compounds of the disclosure canbe administered by any route (e.g., oral, transdermal, transmucosal, orsubcutaneous) to provide after first administration or at steady state,a C_(max), e.g., from about 0.001 ng/mL to about 15 ng/mL, or from about0.005 ng/mL to about 12 ng/mL, or from about 0.05 ng/mL to about 10ng/mL, or from about 0.05 ng/mL to about 1 ng/mL, or from about 0.05ng/mL to about 0.5 ng/mL from about 0.5 ng/mL to about 8 ng/mL, or fromabout 1.0 ng/mL to about 5 ng/mL, or from about 2 ng/mL to about 4ng/mL.

In some embodiments, the buprenorphine compounds of the disclosure canbe administered by any route (e.g., oral or transdermal or subcutaneous)to provide after first administration or at steady state, a C_(n,ax),e.g., of about 0.001 ng/mL, about 0.01 ng/mL, about 0.1 ng/mL, about 1ng/mL, about 2 ng/mL, about 3 ng/mL, about 4 ng/mL, or about 5 ng/mL.

In some embodiments, the buprenorphine compounds of the disclosure canbe administered by any route (e.g., oral, transdermal, transmucosal, orsubcutaneous) to provide after first administration or at steady state,a C_(max), e.g., of less than about 5 ng/mL, less than about 4 ng/mL,less than about 3 ng/mL, less than about 2 ng/mL, less than about 1ng/mL, less than about 0.1 ng/mL, less than about 0.01 ng/mL, less thanabout 0.001 ng/mL or less than about 0.0001 ng/mL.

In some embodiments, the buprenorphine compounds of the disclosure canbe administered by any route (e.g., oral, transdermal, transmucosal, orsubcutaneous) to provide after first administration or at steady state,an AUC, e.g., from about 0.01 ng/mL per hour to about 100 ng/mL perhour, or from about 0.1 ng/mL per hour to about 75 ng/mL per hour, orfrom about 1.0 ng/mL per hour to about 50 ng/mL per hour, or from about5.0 ng/mL per hour to about 40 ng/mL per hour, or from about 10 ng/mLper hour to about 30 ng/mL per hour.

In some embodiments, the steady state or first administration AUC andC_(max) values disclosed herein can be obtained by any suitable route ofadministration such as transdermal, transmucosal, sublingual, buccal,oral, subcutaneous, intramuscular, or parenteral. A depot injection ofbuprenorphine may be administered by implantation (for example,subcutaneously or intramuscularly) or by intramuscular injection. Insuch formulations, the release of the buprenorphine can be controlled byformulation with a suitable polymeric or hydrophobic material (e.g.,polylactic glycolic acid), an ion exchange resin, or from a sparinglysoluble derivative (e.g., a sparingly soluble salt). In someembodiments, the depot injection provides a dosing interval from about 1day to about 3 months, or about 3 days, about 7 days, about 10 days,about 14 days, about 21 days, about one month, about 6 weeks, or about 2months.

In some embodiments, the methods for treating or preventing a Conditionin an animal in need thereof can further comprise co-administering tothe animal being administered the buprenorphine compounds orcompositions of the disclosure (i.e., a first therapeutic agent) asecond therapeutic agent. In some embodiments, the second therapeuticagent is administered in an effective amount.

A composition of the disclosure is prepared by a method comprisingadmixing a buprenorphine compound of the disclosure or apharmaceutically acceptable salt or solvate thereof with apharmaceutically acceptable carrier or excipient. Admixing can beaccomplished using methods known for admixing a compound and apharmaceutically acceptable carrier or excipient. In one embodiment, thebuprenorphine prepared from an acetate salt is present in thecomposition in an effective amount.

Throughout the disclosure when the wt % of buprenorphine free base, anacetate salt of buprenorphine, a hydrate of buprenorphine acetate,buprenorphine acetate tetrahydrate, and/or various impurities isreferred to, the wt % is determined via HPLC purity, for example, by themethod of Example 7 set forth herein.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, that would be within the purview of those skilled inthe art, and changes in formulation or changes in experimental design,are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

Various features and embodiments of the disclosure are illustrated inthe following representative examples, which are intended to beillustrative, and not limiting.

Example 1: Acid Screening Experiments with Buprenorphine Free Base

Buprenorphine free base can be thought of as an organic amine/phenol,which can be treated with acid or base to form its correspondingammonium salt or phenolate salt. It is potentially advantageous to formsuch a salt for purification purposes due to differences in physicalattributes (e.g., solubility) between the salts of the product and theimpurities of interest. The purified salt can then be treated with base(or acid for the phenolate) to regenerate the desired buprenorphine freebase.

Purification of buprenorphine via the hydrochloride salt. Conversion ofbuprenorphine free base to its hydrochloride salt, and back to the freebase was explored. No significant purge of the compound of formula (12)or the compound of formula (14) was observed under any of the conditionsexplored.

To further expand the study of purification of buprenorphine free basevia salt formation, other acids were explored. These included aceticacid, formic acid, trifluoroacetic acid, phosphoric acid, tartaric acid,toluenesulfonic acid, propionic acid, and methane sulfonic acid. For thescreening of these other acids, removal of only the impurity compound offormula (12) was studied.

Procedure for Acid Screening Experiments. In a 20 mL scintillation vial,buprenorphine free base (1.0 g) was dissolved or suspended in eitherwater, an organic solvent, or a mixed organic and aqueous solventfollowed by addition of acid. If necessary to achieve dissolution, themixture was heated on a pie-block heating system up to 80° C. andallowed to cool slowly to a temperature of about 25° C. If crystallinematerial, i.e., a buprenorphine salt, was observed, the solids werefiltered, washed with water, and dried under sub-atmospheric pressure inan oven at 80° C. for about 16 hours and the % recovery relative to theoriginal 1.0 g buprenorphine free base charge was determined. Table 3summarizes the results. For the acids that are solids at a temperatureof about 20° C., i.e., tartaric acid and toluenesulfonic acid hydrate,the mass of acid used is provided instead of the acid volume.

TABLE 3 Acid Screening Experiments with Buprenorphine Free Base FinalAcid:Solvent Composition % Acid Solvent (mL:mL) Recovery ObservationsAcetic Acid Water 2.5:15  80 Crystals formed Acetic Acid Water  4:24 74First repeat experiment, crystals formed Acetic Acid Water  4:24 82Second repeat experiment, crystals formed Acetic Acid Water  4:24 78Third repeat experiment, crystals formed Trifluoroacetic Water 2:2 — Nocrystallization, oil formed at Acid 25° C. Phosphoric Acid Water 1:3 —No crystallization on cooling, (85%) remained in solution at 25° C.Tartaric Acid Water (1:4 Water:IPA) — No crystallization (0.32 g) andIPA p-Toluenesulfonic Water (1:4 Water:IPA) — No crystallization, hazyAcid Hydrate and IPA solution (0.41 g) Sulfuric Acid Water 1:3 — Nodissolution, decomposed at 0° C.-65° C. Formic Acid IPA 1:5 — Nocrystallization Formic Acid Water  3:12 61 Crystals formed PropionicAcid Water  3:12 — No crystallization, oil formed Methanesulfonic Water4:4 — No crystallization Acid Methanesulfonic Water 1:(1:6 — Nocrystallization Acid (1 mL) and IPA Water:IPA)

Acetic acid or formic acid resulted in the formation of crystals;addition of the other acids failed to form filterable salts. However, inorder to achieve crystallization of the buprenorphine salt when usingeither acetic acid or formic acid, it was discovered that the volume ofwater used should be about the same as the volume of acid used tofacilitate dissolution of the buprenorphine free base. Thereafter, theaddition of a greater quantity of water brought about crystallization ofa buprenorphine salt. For example, for the addition of acetic acid inTable 3 above that achieved 80% recovery, initially 2.5 mL of aceticacid and 2.5 mL of water were added so that the buprenorphine free basecould dissolve. Thereafter, at a temperature of about 25° C., adding anadditional 12.5 mL of water brought about crystallization of thebuprenorphine acetate salt.

In addition, only the two aqueous mixtures containing either acetic acidor formic acid offered a promising purge of the impurity of the compoundof formula (12) (up to 40%). Recovery of the corresponding salt ofbuprenorphine was higher from aqueous mixtures of acetic acid (78.5%,average of four determinations) than from formic acid (61%). In bothcases, the corresponding salt of buprenorphine was isolated as acrystalline solid. The other acids provided the corresponding salts ofbuprenorphine, if any, as an oil or gum which was not amendable toisolation via filtration. Interestingly, it was discovered that thesolids isolated from acetic acid:water yielded buprenorphine free baseupon drying under sub-atmospheric pressure at elevated temperature(e.g., 85° C.). Without being bound by theory, this discovery wasbelieved to suggest a somewhat weak association between acetic acid andbuprenorphine and the phenomenon was developed into an advantageousisolation of buprenorphine free base by a purification process involvingaqueous acetic acid (see, e.g., Examples 2 and 8 below). Repeated acidscreening determinations for the acetic acid:water solvent systemconfirmed that crystallization from acetic acid:water led to anadvantageous increased purging of the compound of formula (12).

Example 2: Preparation of Buprenorphine Acetate Salt

For preparing the buprenorphine acetate salt, buprenorphine free base(100 gm, 214 mmol) was dissolved in 1:1 acetic acid:water (vol:vol, 370mL). The temperature during addition of the acetic acid-water solutionwas maintained at 60° C. Still at 60° C., the mixture was then polishfiltered, i.e., filtered to remove non-product related insolubleimpurities (e.g., dust). The dissolution equipment was then rinsed with0.4 volumes of 51 wt % acetic acid in water and the rinse and thefiltrate were combined.

Crystallization: At 60° C., about 0.75 volumes (75 mL) of water(anti-solvent) were added to the combined filtrate at a rate of 8mL/min. The resulting admixture was seeded with 0.5 g of buprenorphineacetate salt crystals. The solution was held at 60° C. for 0.5 hrs, andthen about 5.9 volumes (588 mL) of water (anti-solvent) were added at arate of about 15 mL/min. at a temperature of 60° C. Thereafter, about0.9 volumes (88 mL) of IPA at a temperature of 60° C. were added and themixture was cooled at a rate of 8° C./hour to 20° C. to provide aprecipitate.

Isolation of Buprenorphine Acetate: The precipitate from thecrystallization step was filtered and washed with 2.5 volumes of 17 wt %IPA in water. The precipitate was then washed a second time with 17 wt %IPA in water at 20° C.

Example 3: Buprenorphine Acetate Tetrahydrate Crystal Structure bySingle Crystal X-Ray Analysis

A colorless, prismatic single crystal of [C₂₉H₄₂NO₄]⁺[CH₃COO]⁻.4H₂O withthe approximate dimensions of 0.24 mm×0.10 mm×0.05 mm, obtained by amethod substantially equivalent to that of Example 2 but modified tofacilitate the growth of dimensionally-larger crystals, was mounted on aMICROMOUNT and centered on a R-AXIS RAPID X-ray diffractometer (RigakuAmericas, Woodlands, Tex.).

Diffraction data were acquired at a temperature of about 25° C. on theabove diffractometer equipped with a sealed tube copper source(λ=1.54187 Å) and a Spider curved image plate detector. Four framesseparated in reciprocal space were recorded to provide an orientationmatrix and initial cell parameters. Final cell parameters were obtainedand refined based on the full data set. A diffraction data set ofreciprocal space was obtained to a resolution of 0.81 Å using 5°oscillation steps and 300 s exposure for each frame. Integration ofintensities and refinement of cell parameters were accomplished usingCRYSTALCLEAR software. Observation of the crystal after data collectionand the appearance of diffraction rings on the recorded images indicatedthat the crystal underwent slow decomposition during the diffractionexperiment.

The structure was solved using OLEX2 (Dolmanov et al., “Olex2: acomplete structure solution, refinement and analysis program,” J ApplCryst. 42:339-341 (2009)) with the OLEX2.SOLVE structure solutionprogram (Puschmann et al., “[MS45-P09] Olex2—a complete package formolecular crystallography,” Acta Cryst. A 69:s679 (2013)) with chargeflipping method, and refined with the OLEX2.REFINE refinement package(Bourhis et al., “The anatomy of a comprehensive constrained, restrainedrefinement program for the modern computing environment—Olex2dissected,” Acta Cryst. A 71:1-17 (2014)) using Gauss-Newton full matrixminimization.

Based on systemic absences and intensities statistics, the structure wassolved and refined in a non-centrosymmetric monoclinic P2₁ space group.Non-hydrogen atoms were found by the charge flipping method used forsolving the structure and were refined using anisotropic atomicdisplacement parameters. The hydrogen atoms were placed in calculatedpositions and were refined with isotropic atomic displacementparameters. The structure had two cations of buprenorphine and twoacetic acid anions as well as eight water molecules in the unit cellmaking one cation of buprenorphine, one acetic acid anion, and fourwater molecules symmetry independent.

Packing of the molecules in the crystal was determined by strongCoulombic interaction between the buprenorphonium cation and acetic acidanion well as nine distinct hydrogen bonds (“HB”) between thebuprenorphonium cation, acetic acid anion, and water molecules.

Three strong HBs were present in the structure. One HB, denoted by “A”in FIG. 1, was an intramolecular hydrogen bond between the aliphatichydroxyl group (containing the oxygen atom labeled as “O23” in FIG. 3)and the oxygen atom of the methoxy group of the buprenorphine (labeledas “O21” in FIG. 3); the intramolecular HB length was 2.569 Å. AnotherHB, denoted by “B” in FIG. 1, was an intermolecular HB formed betweenthe hydrogen of the nitrogen cation of the buprenorphine (HB donor,labeled as “N1” in FIG. 3) and one of the oxygen atoms of the aceticacid anion (HB acceptor, labeled as “O42B” in FIG. 3); theintermolecular HB length was 2.681 Å. The third HB, denoted by “C” inFIG. 1, was another intermolecular HB between a water molecule oxygen(labeled as “O1” in FIG. 3) and the phenol group (HB donor, containingthe oxygen atom labeled as “O11” in FIG. 3). The length of this bond was2.591 Å, indicating a strong interaction.

The acetic acid anion was also involved in formation of other HBs toadjacent water molecules. The HB distances of these three interactionswere 2.735 Å (acetic acid anion to the water molecule containing O1),2.743 Å (also to the water molecule containing O1 from another watermolecule), and 2.778 Å (acetic acid anion to a hydrogen of the watermolecule containing the oxygen atom labeled as “O4” in FIG. 3).

The aliphatic hydroxyl group of the buprenorphine acted as a HB acceptoras well, forming a HB, denoted by “D” in FIG. 1, with an adjacent watermolecule (containing O4) acting as a HB donor. The HB length of thisinteraction was 2.802 Å, significantly longer than for theintramolecular hydrogen bond A.

The phenol group was also involved in formation of two intramolecularhydrogen bonds—both with adjacent water molecules. One of the twohydrogen bonds, the HB with oxygen atom O1 previously identified as “C”in FIG. 1, was significantly shorter (2.591 Å) and therefore strongerthan the HB formed with oxygen atom labeled as “O2” in FIG. 3 (3.007 Å).

All four water molecules were involved in formation of differenthydrogen bonds; three of them were saturated, i.e., each formed threeHBs—two as a donor and one as an acceptor. One water molecule(containing the oxygen atom labeled as “O3” in FIG. 3) was involved information of only one HB (with another water molecule containing O2).Without being bound by theory, it is believed that the O3-containingwater molecule would be most susceptible to leaving the crystal latticeduring a dehydration process, that water molecule being the most looselybound of the four water molecules.

Water molecule 1 (containing O1) formed two HBs with two acetic acidanions and accepted a HB from the phenolic hydroxyl group of thebuprenorphine. Water molecule 2 (containing O2) formed two HBs with twoother water molecules and one as a donor with the phenolic hydroxylgroup. Water molecule 3 (containing O3) formed only one HB as a donorwith another water molecule (containing O2). Water molecule 4(containing O4) formed one hydrogen bond with the acetic acid anion, onewith the aliphatic hydroxyl group of the buprenorphine, and accepted HBfrom another water molecule (containing O2).

The density of the crystalline phase at a temperature of about 25° C.was calculated to be 1.2535 g/cm³.

Table 4 summarizes some of the single crystal X-ray analysisdeterminations for buprenorphine acetate tetrahydrate. FIG. 2 shows apacking diagram of buprenorphine acetate tetrahydrate within the unitcell.

TABLE 4¹ Empirical formula C₃₁H₅₃NO₁₀ (Buprenorphine Free (C₂₉H₄₁NO₄₎Base Empirical formula) Formula Weight 599.76 g/mol (Buprenorphine Free(467.64 g/mol) Base Formula Weight) Crystal System Monoclinic SpaceGroup P2₁ a 10.5190 Å [4] b 10.9258 Å [4] c 14.4421 Å [10] α 90° β106.812° [8] γ 90° Volume 1588.87 Å³ [15] Z   2 μ 0.760 mm⁻¹ F (000) 654.2 Radiation Cu Kα (λ = 1.54187 Å) 2Θ range for data 6.4° to 143.42°collection Index ranges −10 ≤ h ≤ 12 −13 ≤ k ≤ 13 −17 ≤ l ≤ 17Reflections collected 22679 Independent reflections 5921 {R_(int) =0.0674, R_(sigma) = 0.1220} Data/restraints/parameters 5921/0/398Goodness-of-fit on F² 1.002 Final R indexes R₁ = 0.0880 {I ≥ 2σ (I)} wR₂= 0.2120 Final R indexes {all data} R₁ = 0.1595 wR₂ = 0.2925 Largestdiff. peak/hole 0.48 e Å⁻³/−0.50 e Å⁻³ Flack parameter −0.0 [4] ¹Eachnumber within square brackets is the estimated standard deviation(“ESD”) of the final digit of the reported value. For example, for thereported unit cell parameter a-axis length of 10.5190 Å, the ESD is±0.0004 Å.

The single crystal of buprenorphine acetate tetrahydrate analyzed hadthe fractional atomic coordinates (×10⁴) and equivalent isotropicdisplacement parameters (Å²×10³) set forth in Table 5. FIG. 3 shows astick representation of the components of the buprenorphine acetatetetrahydrate crystal including the atom numbering scheme used in Table5.

TABLE 5¹ Atom x y z U (eq.) C2 −11486 [7] −7262 [6] −8543 [5] 43.4 [18]C3 −10066 [7] −7107 [7] −8580 [5] 45.1 [19] C4 −9781 [7] −5849 [6] −8948[4] 37.6 [17] C5 −10116 [7] −4823 [6] −8322 [5] 39.5 [17] C6 −11604 [7]−5009 [7] −8404 [4] 40.3 [17] C7 −12513 [7] −4872 [6] −9458 [4] 42.1[18] C8 −11892 [7] −5216 [6] −10244 [5] 39.5 [17] C9 −12434 [8] −4973[7] −11209 [5] 46.8 [19] C10 −11668 [9] −5073 [7] −11865 [5] 57 [2] C11−10333 [8] −5303 [6] −11539 [5] 39.3 [17] C12 −9791 [7] −5532 [6] −10571[5] 37.6 [16] C13 −10587 [7] −5597 [6] −9966 [4] 37.4 [16] C15 −8345 [7]−5742 [7] −9030 [4] 39.3 [18] C16 −7708 [7] −4620 [7] −8422 [5] 43.8[18] C17 −7651 [7] −5006 [6] −7370 [4] 38.6 [16] C18 −9111 [7] −4865 [7]−7290 [5] 46.3 [19] C19 −9930 [7] −3581 [7] −8719 [5] 44.2 [19] C20−8502 [8] −3492 [7] −8790 [5] 48 [2] C22 −5979 [10] −3712 [9] −9069 [7]84 [3] C23 −6568 [8] −4426 [7] −6512 [5] 48 [2] C24 −6608 [9] −3032 [7]−6492 [6] 58 [2] C25 −6513 [8] −5000 [7] −5492 [5] 49 [2] C26 −6655 [9]−6384 [8] −5559 [6] 65 [3] C27 −7523 [9] −4455 [9] −5026 [6] 66 [3] C28−5097 [9] −4800 [9] −4793 [6] 68 [3] C29 −13208 [8] −6380 [8] −7886 [6]58 [2] C30 −13484 [9] −7552 [9] −7434 [5] 61 [3] C31 −14891 [9] −7909[7] −7589 [6] 57 [2] C32 −14048 [10] −8593 [9] −8062 [8] 78 [3] N1−11820 [6] −6237 [5] −7983 [4] 42.3 [15] O11 −9523 [6] −5289 [5] −12126[3] 54.6 [14] O14 −8470 [5] −5666 [5] −10054 [3] 41.0 [12] O21 −6344 [5]−4584 [5] −8494 [4] 53.0 [14] O23 −5299 [5] −4806 [6] −6660 [4] 61.9[16] C41 −9924 [9] −6962 [9] −4473 [5] 63 [3] C42 −10551 [8] −6292 [8]−5431 [5] 46.5 [19] O42A −11102 [6] −5299 [6] −5449 [4] 67.4 [17] O42B−10479 [5] −6879 [5] −6172 [3] 47.6 [13] O4 −2900 [6] −3593 [6] −6509[5] 74.5 [18] O2 −7198 [10] −6922 [8] −12061 [6] 116 [3] O3 −4259 [8]−1514 [8] −9832 [7] 111 [3] O1 −10640 [8] −4111 [5] −13710 [4] 74.9 [19]¹Each number within square brackets is the ESD of the final digit of thereported value.

Example 4: Buprenorphine Acetate Tetrahydrate Structure by X-Ray PowderDiffraction

To further characterize the crystalline form of buprenorphine acetatetetrahydrate, the powdered compound was analyzed by X-ray diffraction. Arepresentative XRPD pattern obtained from a buprenorphine acetatetetrahydrate sample using CuKα radiation yielded peaks at thediffraction angles (°2θ±0.2°) provided in Table 1 above and is shown inFIG. 4.

The XRPD pattern was collected with an X'Pert PRO MPD diffractometer(PANalytical Inc., Westborough, Mass.) using an incident beam of Curadiation produced using an OPTIX long, fine-focus source. Anelliptically graded multilayer mirror was used to focus CuKα X-raysthrough the specimen and onto the detector. Prior to the analysis, asilicon specimen (National Institute of Standards and Technology(“NIST”) Standard Reference Material 640d, Gaithersburg, Md.) wasanalyzed to verify that the observed position of the Si 111 peak wasconsistent with the NIST-certified position. A specimen of the samplewas sandwiched between 3 μm thick films and analyzed in transmissiongeometry. A beam-stop, short anti-scatter extension, and an anti-scatterknife edge were used to minimize the background generated by air. Sollerslits for the incident and diffracted beams were used to minimizebroadening from axial divergence. The diffraction pattern was collectedusing a X'Celerator scanning position-sensitive detector (PANalyticalInc.) located 240 mm from the specimen and X'Pert Data Collectorsoftware version 2.2b.

Example 5: Differential Scanning Calorimetric Analysis of BuprenorphineAcetate Tetrahydrate

To further characterize buprenorphine acetate tetrahydrate, the compoundwas analyzed by differential scanning calorimetry (“DSC”). Arepresentative DSC curve for a buprenorphine acetate tetrahydrate sampleis shown in FIG. 5.

The DSC of the buprenorphine acetate tetrahydrate samples, presented asheat flow (W/g) vs. temperature (° C.), had two transition regions. Thefirst transition region was from about 50° C. to about 180° C. The peakor peaks in this region were broad with one or more minima and likelyrepresented the loss of water and/or acetic acid from the materialsample being analyzed. The second transition region was from about 210°C. to about 225° C. This region featured a sharp transition that waslikely representative of the melting of buprenorphine base. This sharptransition was also present at about the same peak temperature in theDSC of the free base form of buprenorphine.

Several samples of buprenorphine acetate tetrahydrate of varying sizeswere analyzed for consistency between different sample sizes. DSCanalysis was performed using a linear heating ramp of 10° C./minute to250° C. The measurements were determined with a Q20 DSC apparatus (TAInstruments, New Castle, Del.). The integrals (area under the curve) ofthe transition regions (Region 1/Region 2) were determined by TAInstruments Universal Analysis 2000 software (version 4.5A, build4.5.0.5) over the temperature range of from about 35° C. to about 180°C. for the first transition region and from about 203° C. to 233° C. forthe second transition region. The integral ratios of the transitionregions are shown in Table 6 below. A representative DSC profile, forLot 2 discussed below, is shown in FIG. 6. As can be noted from FIG. 6,for this determination Region 1 extended from point “A” at about 35.5°C. to point “B” at about 178° C. and Region 2 extended from point “C” atabout 206° C. to point “D” at about 231° C.

TABLE 6 Integral Ratios of Buprenorphine Acetate Tetrahydrate DSCRegions Sample Size Region 1 Integral Region 2 Integral Ratio (mg) (J/g)(J/g) (Region 1/Region 2) 2.9 −441.8 −57.5 7.68 6.4 −460.5 −62.5 7.376.9 −477.9 −62.8 7.61 13.7 −451.3 −61.7 7.31

To test for consistency of this integral ratio between buprenorphineacetate tetrahydrate samples, several different sample lots wereanalyzed. DSC analysis was performed using a linear heating ramp of 10°C./minute to 250° C. The results are shown in Table 7.

TABLE 7 Integral Ratios of Buprenorphine Acetate Tetrahydrate DSCRegions, Varying Lots Lot Number Region 1 Integral Region 2 IntegralRatio (mg) (J/g) (J/g) (Region 1/Region 2) Lot 1 (5.4) −462.3 −63.1 7.33Lot 2 (6.9) −477.9 −62.8 7.61 Lot 3 (6.2) −450.6 −63.0 7.15 Lot 4 (6.4)−458.1 −64.3 7.12 Lot 5 (6.9) −466.0 −63.5 7.34 Lot 6 (7.9) −473.4 −65.57.23

The integral ratios of the two regions were similar across a range ofsample sizes. The integral ratios of the two regions were similar acrossa number of samples of buprenorphine acetate. The approximate integralratio of Region 1/Region 2 for the buprenorphine acetate tetrahydratesamples was from 7.0 to about 8.0. In another embodiment, theapproximate integral ratio of Region 1/Region 2 for a buprenorphineacetate tetrahydrate sample is from 7.1 to about 7.9. In anotherembodiment, the approximate integral ratio of Region 1/Region 2 for abuprenorphine acetate tetrahydrate sample is from 7.1 to about 7.7.

Example 6: Buprenorphine Acetate Tetrahydrate Karl Fischer % WaterAnalysis

Thirteen samples of buprenorphine acetate tetrahydrate were measured fortheir water content by Karl Fischer (“KF”) titration analysis. KFanalysis methodologies are known in the art, for example, see ASTMStandard E203-08 (“Standard Test Method for Water Using Volumetric KarlFischer Titration”) and ISO 760:1978 (“Determination of Water-KarlFischer Method”). A compilation of the KF values for various samples ofbuprenorphine acetate tetrahydrate are tabulated below. The tablerepresents a number of samples generated from a variety ofcrystallization conditions and dried at a temperature of about 25° C.and a pressure of about 1 atm to a constant weight. The KF titrationswere carried out using a 915 KF Ti-Touch apparatus (Metrohm USA Inc.,Riverview, Fla.) with HYDRANAL Composite 5 Karl Fischer reagent(Sigma-Aldrich, St. Louis, Mo.). The results are shown in Table 8 below.The mean of the thirteen determinations is also provided in Table 8along with the theoretical weight percent of water (12.02 wt %)calculated for the tetrahydrate of buprenorphine acetate.

TABLE 8 KF Determination Sample No. (Wt % Water) 1 12.52 2 11.80 3 11.834 11.84 5 12.47 6 12.39 7 12.76 8 12.94 9 12.28 10  12.50 11  11.98 12 12.02 13  12.18 Mean 12.27 Theoretical 12.02

The mean value of wt % water for the 13 different buprenorphine acetatehydrate samples tested differed from this theoretical value by only 0.25wt % water or by only about 2.1%.

Example 7: HPLC Analysis Procedure

A Waters 2695 HPLC (Waters Corp., Milford, Mass.) with a reversed-phase100 mm×3.0 mm inner diameter GEMINI NX-C18 column, 3.0 μm particle size(Phenomenex, Torrance, Calif.) was used. The detection wavelength was240 nm. A gradient mobile phase utilized 20 mM aqueous ammoniumbicarbonate at pH 9.0 (“MPA”, 99.5%, Fluka, St. Louis, Mo.) as mobilephase A and acetonitrile (“MPB”, 99.9%, Sigma-Aldrich, St. Louis, Mo.)as mobile phase B according to the gradient profile provided in Table 9.

TABLE 9 Time from Volume % Volume % Step Injection (min.) MPA MPB 1 0.0080.0 20.0 2 6.00 50.0 50.0 3 22.00 40.0 60.0 4 35.00 10.0 90.0 5 40.1080.0 20.0

The column temperature was 40° C., the injection volume was 15 μL, andthe flow rate was 1.0 mL/min. Analysis concluded at about 45 minutesafter each injection.

Each buprenorphine acetate tetrahydrate sample was prepared for HPLCanalysis as follows. In duplicate, 100.0±2.0 mg of sample was weighed,the weight was recorded (W_(S) is the weight of each sample), and thesample was quantitatively transferred into a 100 mL volumetric flask.About 50 mL of methanol (99.9%, Fisher Scientific, Pittsburgh, Pa.) wasadded to the flask and the admixture was sonicated and/or vortex mixedas required until all solids appeared to be dissolved. Thereafter,additional methanol was added to the mark and the solution was mixedwell.

Standard solutions were prepared as follows. A working standard solutionwas prepared by weighing 27.0±1.0 mg of USP buprenorphine hydrochlorideCIII reference standard (#1078700, USP, Rockville, Md.) of known purity,recording the weight (W_(STD) is the weight of the USP standardcorrected for purity), and quantitatively transferring it into a 25 mLvolumetric flask. About 15 mL of methanol was added to the flask and theadmixture was sonicated and/or vortex mixed as required until all solidsappeared to be dissolved. Thereafter, additional methanol was added tothe mark and the solution was mixed well. The working standard solutioncontained the equivalent of 1.0 mg/mL of buprenorphine free base. Theworking standard was used to verify that, inter alia, the retentiontime, tailing factor, and repeatability of the buprenorphine peak wasacceptable. An intermediate standard solution was prepared by pipetting2.5 mL of working standard solution into a 50 mL volumetric flask,diluting to volume with methanol, and mixing well. The intermediatestandard solution contained the equivalent of 0.05 mg/mL ofbuprenorphine free base. A sensitivity standard solution was prepared bypipetting 1.0 mL of intermediate standard solution into a 100 mLvolumetric flask, diluting to volume with methanol, and mixing well. Thesensitivity standard solution contained the equivalent of 0.0005 mg/mLof buprenorphine free base. The sensitivity standard was used to verifythat the HPLC signal/noise ratio was not less than 10.

A system suitability standard was prepared as follows. To a container ofthe European Pharmacopoeia reference standard “buprenorphine for systemsuitability” containing 10 mg of material (# Y0001122, EuropeanDirectorate for the Quality of Medicines & Health Care, Strasbourg,France) was added about 2 mL of methanol. The container was capped,shaken and inverted several times so as to rinse it and dissolve allsolids, and the solution was transferred into a 10 mL volumetric flask.This dissolution procedure was repeated twice more. The about 6 mL ofsolution was sonicated for about 5 min. to insure dissolution of allsolids, cooled to a temperature of about 25° C., diluted to volume withmethanol, and mixed well. The system suitability standard solutioncontained 1.0 mg/mL of buprenorphine free base along with a knownprofile of impurities (see European Pharmacopoeia monographs 1180,1181). The system suitability standard was used to verify that therequired resolution between impurity peaks and the buprenorphine peakwas achieved.

The HPLC column was cleaned and flushed as required and thenequilibrated with 80:20 MPA:MPB for 30 minutes at 40° C. and at a flowrate of 1.0 mL/min. Thereafter, the injection sequence in Table 10 wasfollowed.

TABLE 10 Analyte Number of Injections Methanol (blank) At least 2Sensitivity Standard 1 System Suitability Standard 1 Working Standard 5(for repeatability, final 2 injections for quantitation) Methanol(blank) 1 Sample (bracket up to 6) 1 Working Standard 2 Methanol (blank)1

For each sample peak, the corresponding peak area was determined by theinstrument software to provide the quantity A_(S). The total peak area,A_(TOTAL), was determined by summing the areas of all the peaks, againby the instrument software. If the area of any peak was ≤0.05×A_(TOTAL),the area of that peak was removed from A_(TOTAL) and the processrepeated until no minor peak's contribution was removed from A_(TOTAL).Thereafter, the area % purity, e.g., for the buprenorphine acetatetetrahydrate peak (see, e.g., Tables 11-14 in Example 8), was determinedfrom the ratio of A_(S) for that peak to A_(TOTAL) and calculatedaccording to Equation 1 as follows:

$\begin{matrix}{{{Area}\mspace{14mu} \% \mspace{14mu} {purity}} = {\frac{A_{S} \times 100}{A_{TOTAL}}.}} & \left( {{Equation}\mspace{14mu} 1} \right)\end{matrix}$

Similarly, for each impurity peak, the area % purity for that impuritypeak (see, e.g., Tables 2 and 16) was determined from the ratio of A_(S)for that impurity peak to A_(TOTAL) and calculated using the equationabove. The area % purity for buprenorphine free base (see, e.g., Table16 in Example 9) was also determined in this manner by replacing thebuprenorphine tetrahydrate sample with a buprenorphine free base sample.

In certain instances, the wt % purity of buprenorphine free base wasdetermined by the above-described HPLC analysis procedure (see, e.g.,Table 15 in Example 9). Quantitation of buprenorphine free base wasachieved by comparison of its response with the HPLC response of theabove-described USP buprenorphine hydrochloride CIII external referencestandard. Wt % purity was calculated according to Equation 2 as follows:

$\begin{matrix}{{{Wt}\mspace{14mu} \% \mspace{14mu} {purity}} = {\frac{A_{S^{*}} \times W_{STD} \times 0.9277 \times 4}{A_{STD} \times W_{S^{*}}} \times 100}} & \left( {{Equation}\mspace{14mu} 2} \right)\end{matrix}$

where:A_(S)*=Peak area of buprenorphine free base in the sample,A_(STD)=Average peak area of working standard used for quantitation,W_(S)*=Weight (in mg) of buprenorphine free base in the sample, andW_(STD)=Weight (in mg) of standard, corrected for purity.

In Equation 2, the quantity “4” is the dilution factor; the quantity“0.9277” is the molecular weight ratio of buprenorphine free base to thebuprenorphine HCl salt standard; and the quantity “100” is theconversion factor used to obtain the percentage purity.

The quantitative determination of an impurity or an unknown in a samplewas achieved by calculating its wt % in the sample according to Equation4 as follows:

$\begin{matrix}{{{Wt}\mspace{14mu} \% \mspace{14mu} {{impurity}/{unknown}}} = {\frac{A_{I/U} \times W_{STD} \times 0.9277 \times 4}{A_{STD} \times W_{I/U} \times {RRF}_{I/U}} \times 100}} & \left( {{Equation}\mspace{14mu} 3} \right)\end{matrix}$

where:A_(I/U)=Peak area of impurity or unknown in the sample,W_(I/U)=Weight (in mg) of sample containing impurity or unknown, andRRF_(I/U)=Relative response factor of the impurity or unknown.

In Equation 3, the quantities A_(STD) and W_(STD) are as defined abovefor Equation 2. Relative response factors, e.g., RRF_(I/U), areroutinely determined by methods known to those in the art; see, forexample, Gordon et al., “Relative Response Factor for Lamivudine andZidovudine Related Substances by RP-HPLC with DAD Detection,” Chem.Materials Res. 6(12):160-165 (2014).

The calculations of Equations 1, 2 and 3 were performed automatically bythe EMPOWER software provided with the Waters HPLC instrument used inthis example.

Example 8: Stability Analysis of Buprenorphine Acetate Tetrahydrate

Samples of buprenorphine acetate tetrahydrate were analyzed initiallyand after 1 month and 3 months of aging. Each tested sample was preparedby weighing about a 300 mg sample of buprenorphine acetate tetrahydrate,obtained by the method described in Example 2, into a stability bagtransparent to visible and UV light (ARMORFLEX Model # SB4016-01, ILCDover, Frederica, Del.). Each bag was sealed using a heated bag sealer.Following exposure under one of the stability test conditions specifiedbelow, the sample was removed and analyzed for area % purity by HPLC asdescribed in Example 7.

Duplicate results for each aging sample were averaged to provide thearea % purity results reported in Tables 11-14 below.

Long term aging stability for buprenorphine acetate tetrahydrate wasdetermined in darkness under stability chamber conditions of 25° C. and60% humidity. Samples were examined at time periods of 0, 1, and 3months. The results are shown in Table 11.

TABLE 11 Long Term Aging - Area % Purity Initial = Month #0 Month #1Month #3 99.9% 99.9% 99.9%

The buprenorphine acetate tetrahydrate was stable, with nodeterioration, for up to 3 months under long term aging conditions.

Accelerated aging stability for buprenorphine acetate tetrahydrate wasexamined in darkness under stability chamber conditions of 40° C. and75% humidity. Samples were examined at time periods of 0, 1, and 3months. The results are shown in Table 12.

TABLE 12 Accelerated Aging - Area % Purity Initial = Month #0 Month #1Month #3 99.9% 99.9% 99.9%

The buprenorphine acetate tetrahydrate was stable, with nodeterioration, for up to 3 months under accelerated aging conditions.

Photostability for buprenorphine acetate tetrahydrate was examined in aCaron stability chamber under the conditions of 25° C. and 60% humidity.For testing aging stability in UV light, samples were exposed to UVlight from a TL 20W/12RS UV bulb (Philips Lighting) at an intensity of21.9 W/m² continuously for time periods of 0, 1, and 3 months. Fortesting aging stability in visible light, samples were exposed tovisible light from a F24T12/CW/HO fluorescent bulb (Philips Lighting)with an intensity of 27 K lux continuously for time periods of 0, 1, and3 months. The results are shown in Tables 13 and 14 below, respectively.

TABLE 13 Aging in the Presence of UV Light - Area % Purity Initial =Month #0 Month #1 Month #3 99.9% 99.9% 99.8%

TABLE 14 Aging in the Presence of Visible Light - Area % Purity Initial= Month #0 Month #1 Month #3 99.9% 99.8% 99.8%

The buprenorphine acetate tetrahydrate was stable to UV and visiblelight for up to 3 months, with only a 0.1 area % change in purity.

Example 9: Preparation of Buprenorphine Free Base

Method 1: Purified buprenorphine free base was prepared as follows fromapproximately 100 g of crude buprenorphine free base (“100 g Batch”). Toa wet filter cake of buprenorphine acetate tetrahydrate (approximately109 g, approximately 182 mmol, prepared by the method in Example 2 fromcrude buprenorphine free base) in a model FD100-C22 laboratory filterdrier (GL Filtration Ltd., Rossington, Doncaster, UK) was charged apre-mixed solution of water (120 mL), IPA (180 mL), and aqueous ammoniumhydroxide (28 wt % ammonia in water, 19.5 g, 1.7 equivalents). Theresulting slurry was stirred at 35° C. for 4 hours and filtered. To theisolated wet solids was charged a second portion of a pre-mixed solutionof water (120 mL), IPA (180 mL), and aqueous ammonium hydroxide (28 wt %ammonia in water, 19.5 g, 1.7 equivalents). The resulting slurry wasstirred at 35° C. for 4 hours and filtered. The isolated solids werecooled to a temperature of about 25° C., re-slurried twice in 80:20water:IPA (200 mL), and filtered. The solids were dried in the filterdrier under reduced pressure (150 Torr) at 70° C. for 8 hours to providebuprenorphine free base as a purified white powder (78.3 g, 92% yield).

Purified buprenorphine free base was prepared from approximately 65 kgof crude buprenorphine free base (“65 kg Batch”) by scaling up Method 1described above.

The purified buprenorphine free base obtained from each of the abovepreparations was analyzed for the wt % content of its constituents (wt %purity for the purified buprenorphine free base itself) by the HPLCprocedure provided in Example 7. The results are shown in Table 15.

TABLE 15 Weight % 65 kg Analyte Starting Material 100 g Batch BatchCompound of Formula (13) ND ND ND Compound of Formula (10) ND ND NDCompound of Formula (15) ND ND ND Compound of Formula (14) 0.07% 0.08%0.07% Compound of Formula (11) ND ND ND Compound of Formula (12) 0.10%0.05% 0.05% Unknown Impurity <0.05%  ND ND Total Impurities 0.17% 0.13%0.12% Assay 99.7% 99.5% 100.1% 

Method 2: To a model FD100-C22 laboratory filter drier outfitted with anitrogen mass flow controller, vacuum pump, and fluid-filled heatingjacket was charged buprenorphine acetate tetrahydrate as a solid (109.82g, prepared by a method substantially equivalent to the method inExample 2). The system was sealed and placed under the reduced pressureof 150 Torr. The nitrogen flow rate was then set to 200 mL/min, thesystem was supplied with 65° C. heating fluid, and held at temperaturefor 30 minutes. Next, the system was supplied with heating fluid thatwas gradually heated from 65° C. to 95° C. over a period of 6 hrs.Thereafter, the system was supplied with 95° C. heating fluid for 24hrs. The batch temperature of the solids ranged between 67° C. and 70°C. during the 24 hour period. Upon cooling to 20° C., the resultingbuprenorphine free base was discharged as a white solid (83.61 g, 97%yield).

The purified buprenorphine free base obtained above was analyzed for thearea % content of its constituents (area % purity for the purifiedbuprenorphine free base itself) by the HPLC procedure provided inExample 7. The results are shown in Table 16.

TABLE 16 Area % Analyte Starting Material Product Compound of Formula(10) ND 0.01 Unknown Impurity 0.40 0.02 Compound of Formula (14) ND 0.01Buprenorphine Free Base 99.41  99.79 Unknown Impurity 0.08 0.07 Compoundof Formula (12) 0.08 0.07 Unknown Impurity ND 0.01 Unknown Impurity ND0.01

Method 3: To a dissolution vessel containing solid buprenorphine acetatetetrahydrate (approximately 214 mmol) is charged IPA (5 volumes based onthe buprenorphine acetate tetrahydrate charge) and the admixture isheated to 70° C. to dissolve the solids. The resulting solution ispolish filtered using a 0.2 μm polypropylene filter medium and ischarged into a crystallization vessel. IPA (2 volumes) is added to rinsethe dissolution vessel, the rinse solution is heated to 70° C., and thenpolish filtered. The resulting filtered rinse solution is also chargedinto the crystallization vessel and the vessel contents are maintainedat a temperature of 60° C. throughout. Through an addition funnel,aqueous ammonium hydroxide (28 wt % ammonia in water, 19.5 g, 1.5equivalents) is charged into the crystallization vessel. Theanti-solvent, water (5 volumes based on the buprenorphine acetatetetrahydrate charge), is next continuously added to the crystallizationvessel over a 20 minute period while maintaining a batch temperature of60° C.; buprenorphine free base product precipitates. The precipitate isslurried for an additional 30 minutes and the slurry is filtered at abatch temperature of 60° C. to provide buprenorphine free base assolids. The solids are re-slurried twice in 80:20 water:IPA (2 volumes)to remove ammonium acetate and filtered to provide buprenorphine freebase as a white solid. The solids are dried in a vacuum drying ovenunder sub-atmospheric pressure (150 Torr) at 70° C. for 8 hrs to providethe purified buprenorphine free base as a white powder. An almostidentical experiment had a 93% yield.

Method 4: Buprenorphine acetate tetrahydrate (1.00 g) was heated inwater (10 mL) in a capped vial at 80° C. for three hours. The slurry wasfiltered hot, and washed twice with 2 mL of warm water (50° C.). Theproduct, the buprenorphine free base, was dried in air (0.61 g, 78%yield). ¹H NMR (CD₃OD) confirmed the product was the free base, with atrace of acetic acid.

Method 5: Buprenorphine acetate tetrahydrate (10.53 g) was charged intoa flask containing heptane (60 mL), where the flask was outfitted with aDean-Stark trap. The solution was refluxed for 3.5 hrs; the refluxtemperature ranged from 86° C. to 99° C. The trap collected 1.85 mL ofliquid (the theoretical amount of acetic acid and water was 2.2 mL). Themixture was cooled, filtered, washed with heptane, and dried in air toafford the free base form (8.00 g, 98% yield). ¹H NMR (CD₃OD) confirmedthe product was the free base, with a trace of acetic acid.

The invention is not to be limited in scope by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

All publications, patents, patent applications and other documents citedin this application are hereby incorporated by reference in theirentireties for all purposes to the same extent as if each individualpublication, patent, patent application or other document wereindividually indicated to be incorporated by reference for all purposes.

1.-99. (canceled)
 100. A method for preparing buprenorphine free base,comprising treating an acetate salt of buprenorphine at a pressure,temperature and for a period of time sufficient to form buprenorphinefree base.
 101. The method of claim 100, wherein the pressure rangesfrom about 100 Torr to about 200 Torr, inclusive, the temperature is atleast about 30° C. and the period of time is at least about 1 hour. 102.(canceled)
 103. The method of claim 101, wherein the temperature of theacetate salt of buprenorphine is at least about 50° C. and the period oftime is at least about 10 hours.
 104. The method of claim 101, whereinthe temperature of the acetate salt of buprenorphine is at least about65° C. and the period of time is at least about 5 hours. 105.-106.(canceled)
 107. The method of claim 100, further comprising slurryingthe buprenorphine free base with a slurrying solution comprising waterand an alcohol, and filtering the buprenorphine free base therefromwherein the temperature of the buprenorphine free base during theslurrying and the filtering is at least about 50° C. 108.-111.(canceled)
 112. The method of claim 100, wherein acetic acid is presentin the buprenorphine free base in an amount of at less than about 0.5 wt% relative to the buprenorphine free base.
 113. A buprenorphine freebase product obtained from the method of claim 100, wherein the productcomprises about 0.08 wt % or less of a compound of formula (12):


114. A pharmaceutical composition comprising the product of claim 113and a pharmaceutically acceptable carrier. 115.-139. (canceled)
 140. Amethod for preparing buprenorphine free base comprising: (a) heating toa temperature of from about 70° C. to about 90° C. an admixture of anacetate salt of buprenorphine and an aqueous solution; and (b) filteringthe admixture.
 141. The method of claim 140, wherein the aqueoussolution consists essentially of water.
 142. The method of claim 140,wherein the aqueous solution comprises a mixture of water and isopropylalcohol. 143.-146. (canceled)
 147. A buprenorphine free base productobtained from the method of claim 140, wherein the product comprisesabout 0.08 wt % or less of an impurity represented by the compound offormula (12):


148. A pharmaceutical composition comprising the product of claim 147and a pharmaceutically acceptable carrier.
 149. (canceled)
 150. A methodfor preparing buprenorphine free base comprising: (a) mixing an acetatesalt of buprenorphine in a solvent to form an admixture; (b) refluxingthe admixture at a reflux temperature and removing the acetate as aceticacid in the vapor phase; (c) cooling the admixture to precipitatebuprenorphine free base; and (d) isolating the buprenorphine free base.151. The method of claim 150, wherein the isolating comprises filtering.152.-153. (canceled)
 154. A buprenorphine free base product obtainedfrom the method of claim 150, wherein the product comprises about 0.08wt % or less of an impurity represented by the compound of formula (12):


155. A pharmaceutical composition comprising the product of claim 154and a pharmaceutically acceptable carrier. 156.-160. (canceled)
 161. Thebuprenorphine free base product of claim 113, wherein the productcomprises about 0.10 wt % or less of an impurity represented by thecompound of formula (13):


162. A pharmaceutical composition comprising the product of claim 161and a pharmaceutically acceptable carrier.
 163. The buprenorphine freebase product of claim 147, wherein the product comprises about 0.10 wt %or less of an impurity represented by the compound of formula (13):


164. A pharmaceutical composition comprising the product of claim 163and a pharmaceutically acceptable carrier.
 165. The buprenorphine freebase product of claim 154, wherein the product comprises about 0.10 wt %or less of an impurity represented by the compound of formula (13):


166. A pharmaceutical composition comprising the product of claim 165and a pharmaceutically acceptable carrier.